TWI417099B - Quinolone and tetrahydroquinoline and related compounds having nos inhibitory activity - Google Patents

Description

Quinolone, tetrahydroquinoline and related compounds inhibiting nitric oxide synthase activity

The field of the invention relates to quinolones, tetrahydroquinolines and related compounds, and their medical use.

The field of the invention relates to quinolones, tetrahydroquinolines and related compounds, and their medical use.

Nitric oxide (NO) has multiple roles in both normal and disease processes, including regulation of blood pressure, nerve conduction, and macrophage defense systems (Snyder et al., Scientific American , May 1992: 68). NO is synthesized by three isoforms of nitric oxide synthase, one of which is structurally oriented to endothelial cells (eNOS), a neuron-like cell (nNOS), and one that causes shape in macrophages. (iNOS). These enzymes are homomeric proteins that catalyze the 5 electron oxidation of L-arginine to produce NO and citrulline. The NO produced by each NOS isomeric isomer has a rather unique role. Excessive stimulation or excessive production of individual NOS isoforms, especially nNOS and iNOS, may be involved in several disorders, including septic shock, arthritis, diabetes, ischemia-reperfusion injury, pain, and various neurodegeneration. Sexual disease (Kerwin et al., J. Med. Chem. 38:4343, 1995), and inhibition of eNOS function can lead to unwanted effects such as enhanced white blood cell and platelet activation, hypertension, and increased atheroma production ( Valance and Leiper, Nature Rev. Drug Disc. 2002, 1 , 939).

NOS inhibitors have the potential to be used as a treatment for multiple disorders. Of course However, preserving the physiologically important nitric oxide synthase function suggests the need to develop an isoform selective inhibitor that preferentially inhibits nNOS more than eNOS.

The invention features a compound having the formula: Wherein Q is (CHR ⁶ ) _1-3 ; R ¹ and each R ^{6 are} independently H, optionally substituted C _1-6 alkyl, optionally substituted C _1-4 alkaryl, optionally Substituted C _1-4 alkaneheterocyclyl, or optionally substituted C _2-9 heterocyclyl; each R ² and R ^{3 are} independently H, Hal, optionally substituted C _1-6 alkyl Optionally substituted C _6-10 aryl, optionally substituted C _1-6 alkaryl, optionally substituted C _2-9 heterocyclyl, hydroxy, optionally substituted C _1-6 Alkoxy, optionally substituted C _1-6 thioalkoxy, (CH ₂ ) _{r 2} NHC(NH)R ^2A , or (CH ₂ ) _{r 2} NHC(S)NHR ^2A , or optionally substituted C _{a 1-4} alkane heterocyclic group, wherein r 2 is an integer of 0 to 2, R ^2A is an optionally substituted C _1-6 alkyl group, a randomly substituted C _6-10 aryl group, optionally substituted C _1-4 alkaryl, optionally substituted C _2-9 heterocyclyl, optionally substituted C _1-4 alkynyl, optionally substituted C _1-6 thioalkoxy, optionally Substituted C _1-4 sulfane aryl, optionally substituted aryl fluorenyl, optionally substituted C _1-4 sulfane heterocyclyl Or an optionally substituted amino group; each R ⁴ and R ^{5 is} independently H, Hal, (CH ₂ ) _{r 2} NHC(NH)R ^2A , or (CH ₂ ) _{r 2} NHC(S)NHR ^2A ; ¹ and Y ^{2 are} each H, or Y ¹ and Y ² are both =0, or Y ¹ and Y ^{2 are} independently H, optionally substituted C _1-6 alkyl, optionally substituted C _{6- 10} aryl, optionally substituted C _1-6 alkaryl, optionally substituted C _2-9 heterocyclyl, hydroxy, optionally substituted C _1-6 alkoxy, optionally substituted a C _1-6 thioalkoxy group, or an optionally substituted C _1-4 alkane heterocyclyl; wherein only one of R ² , R ³ , R ⁴ and R ⁵ is (CH ₂ ) _{r 2} NHC(NH) R ^2A or (CH ₂ ) ₂₄ NHC(S)NHR ^2A ; or a pharmaceutically acceptable salt or precursor thereof.

In certain embodiments, Q is (CHR ⁶ ) _1-3 ; R ¹ and each R ^{6 are} independently H, optionally substituted C _1-6 alkyl, optionally substituted C _1-4 alkane a optionally substituted C _1-4 alkane heterocyclyl, or a randomly substituted C _2-9 heterocyclyl; each R ² and R ^{3 are} independently H, Hal, optionally substituted C _{1 -6} alkyl, optionally substituted C _6-10 aryl, optionally substituted C _1-6 alkaryl, optionally substituted C _2-9 heterocyclyl, or optionally substituted C _{a 1-4} alkane heterocyclic group; each of R ⁴ and R ^{5 is} independently H, (CH ₂ ) _{r 2} NHC(NH)R ^2A , or (CH ₂ ) _{r 2} NHC(S)NHR ^2A wherein Y ¹ and Y ^{2 are} each Is H, or Y ¹ and Y ² are both =O; wherein one of R ⁴ and R ⁵ but not both are H; or a pharmaceutically acceptable salt or precursor thereof.

In some embodiments, Y ¹ and Y ² are both =0 and Q is (CHR ⁶ ) ₂ ; or Y ¹ and Y ^{2 are} each H and Q is (CHR ⁶ ) ₂ ; or both Y ¹ and Y ² are =O and Q is CHR ⁶ ; or Y ¹ and Y ^{2 are} each H and Q is CHR ⁶ ; or Y ¹ and Y ² are both =O and Q is (CHR ⁶ ) ₃ ; or Y ¹ and Y ^{2 are} each H and Q are (CHR ⁶ ) ₃ .

In certain embodiments, R ² , R ³ , R ⁴ or R ⁵ have the formula: Wherein Z is R ^2A , for example wherein R ^2A has the formula: Each X ¹ , X ² , X ⁴ and X ^{5 is} independently selected from: O, S, NR ⁷ , N, or CR ⁸ ; X ^{3 is} selected from: N or CR ⁸ ; R ⁷ is H or optionally Substituted C _1-6 alkyl; R ⁸ is H, Hal, optionally substituted C _1-6 alkyl, hydroxy, optionally substituted C _1-6 alkoxy, or optionally substituted C _1-6 thioalkoxy; wherein at least one of X ¹ , X ² , X ⁴ and X ^{5 is} not CR ⁸ .

R ^2A can also have the following formula: Each of X ¹ and X ^{2 is} independently selected from: O, S, NH, N, or CH; wherein at least one of X ¹ and X ^{2 is} not CH.

For the exemplified compounds, X ¹ is CH and X ² is S.

Exemplary compounds are shown in Table 2.

The invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable excipient.

Another feature of the invention is a method of treating a condition caused by the action of nitric oxide synthase (NOS) in a mammal, such as a human, comprising administering to the mammal an effective amount of a compound of the invention or a medicament thereof An acceptable salt or precursor.

Examples of symptoms that can be prevented or treated include: migraine (with or without aura), chronic tension headache (CTTH), migraine with tenderness, overdose headache, neuropathic pain, AIDS-related neuropathy Pain-, chronic headache, central post-stroke pain (CPSP), drug-induced hyperalgesia (hyperalgesia), or tenderness, acute pain, chronic pain, neuropathy of diabetes, neuropathic pain caused by chemotherapy, chemical dependence or Drug addiction, CNS disorders, neurodegenerative or neurological damage, cardiovascular related symptoms, diabetic nephropathy, inflammatory disease, or gastrointestinal disorders. Specific examples of such symptoms will be described herein. Preferred symptoms are neuropathic pain, CTTH, visceral pain, and IBS.

The method may further comprise administering to the mammal an opioid, an antidepressant, an anti-epileptic, a non-steroidal anti-inflammatory drug (NSAID), an antiarrhythmic agent, a GABA-B antagonist, an alpha-2- Adrenergic receptor synergist, a serotonin 5HT _1B / _1D synergist, an N-methyl-D-aspartate antagonist, a cholecystokinin B antagonist, a substance P antagonist, a primary anti-inflammatory compound, DHP-sensitive L-type calcium channel antagonist, omega-conotoxin-sensitive N-type calcium channel antagonist, P/Q-type calcium channel antagonist, adenosine kinase antagonist, adenosine receptor A ₁ Synergistic agent, adenosine receptor A _2a antagonist, adenosine receptor A ₃ synergist, adenosine deaminase inhibitor, adenosine nucleoside transport inhibitor, vanilloid VR1 receptor synergy Agent, cannabinoid CB1/CB2 synergist, an AMPA receptor antagonist, kainite receptor antagonist, sodium channel blocker, nicotinic acetylcholine receptor antagonist, K _ATP potassium channel, K _v1.4 potassium channel, Ca ²⁺ - activated potassium channel, SK potassium channel, BK potassium channel, IK potassium Channel, KCNQ2/3 potassium channel open agent, muscarinic M3 antagonist, muscarinic M1 synergist, muscarinic M2/M3 part synergist/antagonist, an antioxidant, primary antipsychotic agent, ora dopamine receptor Anti-Parkinson's agent. Specific embodiments of such compounds are provided herein.

Preferably, the compounds of the invention selectively inhibit neuronal nitric oxide synthase (nNOS), particularly more than endothelial nitric oxide synthase (eNOS) or may cause one of nitric oxide synthase (iNOS) or two By.

Preferably, to observe ₅₀ or K _i value for this compound to the IC, at least lower than eNOS and nNOS for / or iNOS 2 times. More preferably, IC ₅₀ or K _i value is low at least 5,20,50, or 100-fold. In one embodiment, the IC ₅₀ or K _i value is between 2 and 100 times. In another embodiment, eNOS IC ₅₀ or K _i of greater than 10 μ M. More preferably, the eNOS IC _{50 is} greater than 20 μM , optimally the eNOS IC ₅₀ or Ki is greater than 30 μM , and the threshold of eNOS may be required to avoid compression of human vascular tissue by any direct eNOS medium.

The exemplified compounds are described herein.

The invention also provides a pharmaceutical composition comprising a compound of the invention, and a pharmaceutically acceptable excipient.

A feature of the invention is the treatment or prevention of a condition in a mammal, such as a human, caused by the action of nitric oxide synthase (NOS), such as nNOS, comprising administering an effective amount of a compound of the invention to the mammal. . Examples of such symptoms include, for example, migraine headache (with and without aura), chronic tension headache (CTTH), migraine with tenderness, overuse of medication, neuropathic pain, AIDS-related neuropathy Pain, chronic pain, post-stroke central pain (CPSP), drug-induced hyperalgesia and/or tenderness, such as opioid-induced hyperalgesia, triptan (5-HT1D/1B synergist)-induced hyperalgesia/tender pain , acute pain, chronic pain, neuropathy of diabetes, trigeminal neuralgia, neuropathic pain caused by chemotherapy (eg paclitaxel, cis-Platin, Doxorubicin, etc.), bone cancer pain, chemical dependence or addiction, such as drug addiction, Cocaine addiction nicotine addiction, methamphetamine-induced neurotoxicity, alcohol tolerance, dependence or withdrawal, or morphine/opioid (opioid) tolerance, dependence, hyperalgesia ( Hyperalgesia) or withdrawal, CNS disorders, including but not limited to epilepsy, anxiety, depression (alone or combined), attention deficit hyperactivity disorder (ADHD), psychopathy (psychosis) or dementia, neurodegenerative diseases or Injury, such as acute spinal cord injury, AIDS-associated dementia, Parkinson's disease, Alzheimer's disease, ALS, Hunter's disease, multiple sclerosis, neurotoxicity or head trauma Cardiovascular related symptoms such as stroke, CABG-associated neurological damage, hypothermic cardiac arrest (HCA), post-stroke pain, ventricular shock, reperfusion injury or vascular dementia, diabetic nephropathy, inflammatory disease such as osteoarthritis or nerve Meta-inflammatory, or gastrointestinal disorders, such as ileostomy-associated diarrhea, Dumping Syndrome, or visceral pain.

The compounds of the present invention can also be used in combination with one or more other therapeutic agents to prevent or treat one of the above symptoms.

Exemplary agents useful in combination with the compounds of the invention, including opioids, antidepressants, anti-epileptics, non-steroidal anti-inflammatory drugs (NSAIDs), antiarrhythmic agents, GABA-B antagonists, alpha-2-adrenergic receptors Synergist, serotonin 5HT _1B/1D synergist, N-methyl-D-aspartate antagonist, cholecystokinin B antagonist, substance P antagonist (NK1), anti-inflammatory compound, DHP-sensitivity L-type calcium channel antagonist, omega-conotoxin-sensitive N-type calcium channel antagonist, P/Q-type calcium channel antagonist, adenosine kinase antagonist, adenosine receptor A ₁ synergist, adenosine receptor A _2a antagonist, adenosine receptor A ₃ synergist, adenosine deaminase inhibitor, adenosine nucleoside transport inhibitor, vanilloid VR1 receptor synergist, cannabinoid CB1/CB2 synergist , AMPA receptor antagonist, kainite receptor antagonist, sodium channel blocker (eg Navl.8 blocker for neuropathic pain), niacin acetylcholine receptor synergist , K _ATP potassium channel, K _v1.4 potassium channel, Ca ²⁺ -activated potassium channel, SK potassium channel, BK potassium channel, IK potassium channel, or KCNQ2/ 3 potassium channel open agent, muscarinic M3 antagonist, muscarinic M1 synergist, muscarinic M2/M3 part synergist/antagonist, and antioxidant. Specific examples of therapeutic agents for use in combination with the compounds of the invention are listed in Table 1. Other classes include CB1/CB2 synergists such as dexanabinol (HU-211), fatty indoleamine hydrolase inhibitors, P2X purinergic blockers, and NGF antagonists.

NMDA antagonists in combination with nNOS inhibitors are particularly useful in the treatment of a number of conditions, such as inflammatory and neuropathic pain, traumatic brain injury, and Parkinson's disease (see Drug Discovery Today 2002: 7 (7) 403-406).

Any of the compounds of the invention may have an asymmetric or chiral center. The present invention contemplates the various stereoisomers and mixtures thereof. Individual stereoisomers of the compounds of the invention can be prepared synthetically from commercially available starting materials including asymmetric or chiral centers, or can be prepared as mirror image isomer compounds, which are then resolved by methods well known to those skilled in the art. Such resolution methods, for example: (1) the (external) racemic mixture of the mirror image isomer, labeled (+/-), added to a chiral auxiliary, recrystallized or chromatographed The resulting non-image isomers (non-image isomers) separate the optically pure product from the auxiliary, or (2) directly separate the optically mirror imaged isomers from the chiral column. The mirror image isomer is conformed to the substituent structure around the chiral carbon atom and is marked with the symbol " R " or " S ". Alternatively, the mirror image isomer is labeled (+) or (-) depending on whether the mirror image isomer solution rotates the polarization in a clockwise or counterclockwise direction.

Geometrically isomers may also be present in the compounds of the invention. The present invention contemplates the various geometric isomers and mixtures thereof resulting from the arrangement of substituents around the carbon-carbon double bonds and labels the isomers in a Z or E configuration. Wherein "Z" represents the substituent on the same side of the carbon-carbon double bond, and "E" represents the substituent on the opposite side of the carbon-carbon double bond. It is also understood that such structures may have tautomeric forms, and that the description of one tautomeric form is equivalent to the description of both, unless otherwise specified. For example, the 脒 structure -C(=NR ^Q )NHR ^T and -C(NHR ^Q )=NR ^T, wherein R ^T and R ^{Q are} different, are equivalent tautomeric structures, and one of them is essentially including the other. .

It is understood that the substituents and substituted forms of the compounds of the present invention can be selected by those of ordinary skill in the art to obtain compounds which are It is technically stable and easily synthesized by techniques well known in the art and by the following methods, starting from readily available starting materials. If a substitution is substantially replaced by more than one group, it is understood that the multiple groups may be on the same or different carbons as long as a stable structural result can be obtained.

Other features and advantages of the invention will be apparent from the description and appended claims.

definition

The terms "acyl" or "alkanoyl" are used interchangeably herein to denote an alkyl group, as defined herein, or a hydrogen bond to a parent molecular group using a carbonyl group, as defined herein, For example: formazan, ethyl ketone, propyl thiol, butyl thiol and the like. The unsubstituted anthracene group includes, for example, 2 to 7 carbons.

The term "C _xy alkaryl" or "C _xy alkylene aryl" as used herein, denotes a chemical substituent -RR', wherein R is an alkylene group having an x to y carbon and R' is a aryl group. The group is as defined elsewhere. Similarly, the term "C _{xy alkylheteroaryl} " or "C _xy alkyleneheteroaryl" means a chemical substituent -RR" wherein R is an alkylene group having an x to y carbon, R "As a heteroaryl group, as defined elsewhere. Other groups whose prefix is "alk-" or "alkylene-" are defined in the same manner. The unsubstituted alkaryl group is, for example, 7 to 16 carbons.

The term "alkalcycloalkyl" denotes a cycloalkyl group bonded to a parent molecular group by an alkylene group.

The term "alkenyl" as used herein, denotes a monovalent straight or branched chain group, unless otherwise specified, to include one or more carbon-carbon double bonds. Of the 2 to 6 carbons, for example, a vinyl group, a 1-propenyl group, a 2-propenyl group, a 2-methyl-1-propenyl group, a 1-butenyl group, a 2-butenyl group and the like.

The term "alkanocyclyl" denotes a heterocyclic group bonded to the parent molecular group by an alkylene group. The unsubstituted alkane heterocyclic group is, for example, 2 to 14 carbon.

The term "alkoxy" denotes a chemical substituent -OR wherein, unless otherwise specified, R is an alkyl group of one to six carbons.

The term "alkoxyalkyl" denotes a monoalkyl group which is substituted with an alkoxy group. Examples of the unsubstituted alkoxyalkyl group include those of 2 to 12 carbons.

The term "alkyl" and the prefix "alk-" as used herein, unless otherwise specified, include straight-chain and branched-chain saturated groups of 1 to 6 carbons. The alkyl group is, for example, methyl, ethyl, n- and i-propyl, n-, second-, iso- and tert-butyl, neopentyl, etc., and may be optionally substituted with 1, 2, 3, or when the alkyl group is 2 carbon or more, substituted with 4 substituents, which are independently selected from the following groups: (1) alkoxy groups of 1 to 6 carbon atoms; (2) 1 An alkylsulfinyl group of up to 6 carbon atoms; (3) an alkylsulfonyl group of 1 to 6 carbon atoms; (4) an amine group; (5) an aryl group; (6) an arylalkoxy group; (7) an aryl fluorenyl group; (8) an azido group; (9) formaldehyde; (10) a cycloalkyl group of 3 to 8 carbon atoms; (11) a halogen; (12) a heterocyclic group; (heterocyclic) oxygen; (14) (heterocyclic) fluorenyl; (15) hydroxy; (16) N-protected amine; (17) nitro; (18) oxy; (19) 3 to 8 a spiroalkyl group of carbon atoms; (20) a thioalkoxy group of 1 to 6 carbon atoms; (21) a mercaptan; (22)-CO ₂ R ^A , wherein R ^{A is} selected from the group consisting of: a) an alkyl group, (b) an aryl group and (c) an alkylaryl group, wherein the alkylene group is 1 to 6 carbon atoms; (23)-C(O)NR ^B R ^C , wherein each R ^B and R ^C is independently, optional group consisting of the following (a) composed of hydrogen, (b) alkyl, (c) aryl and (d) alkaryl Wherein the alkylene group of 1 to 6 carbon ^{_{atoms; (24) -SO 2 R D}} , wherein, R ^D Optional group consisting of (a) alkyl, (b) aryl and (c) alkaryl a group wherein the alkylene group is 1 to 6 carbon atoms; (25)-SO ₂ NR ^E R ^F , wherein each R ^E and R ^F are independently selected from the group consisting of: (a) hydrogen And (b) an alkyl group, (c) an aryl group and (d) an alkaryl group, wherein the alkylene group is 1 to 6 carbon atoms; and (26)-NR ^G R ^H , wherein each R ^G and R ^H is independently selected from the group consisting of: (a) hydrogen; (b) N-protecting group; (c) an alkyl group of 1 to 6 carbon atoms; (d) an alkenyl group of 2 to 6 carbon atoms (e) an alkynyl group of 2 to 6 carbon atoms; (f) an aryl group; (g) an alkylaryl group in which an alkylene group is 1 to 6 carbon atoms; (h) 3 to 8 a cycloalkyl group of carbon atoms; and (i) an alkylcycloalkyl group wherein the cycloalkyl group is 3 to 8 carbon atoms, and the alkylene group is 1 to 10 carbon atoms, but no 2 groups are borrowed It is bonded to the nitrogen atom by a carbonyl group or a sulfonium group.

The term "alkylene" as used herein, denotes a saturated divalent hydrocarbon radical derived by the removal of two hydrogen atoms from a linear or branched saturated hydrocarbon, such as methylene, ethylene, Heteropropylene and the like.

The term "alkylsulfinyl" as used herein, denotes a monoalkyl group bonded to a parent molecular group by a -S(O)- group. The unsubstituted alkyl sulfoxide group is, for example, one to six carbons.

The term "alkylsulfonyl" as used herein, denotes a monoalkyl group bonded to a parent molecular group by a -SO ₂ - group. The unsubstituted alkylsulfonyl group is, for example, one to six carbons.

The term "alkylsulfinylalkyl" as used herein, denotes an alkyl group, as defined herein, substituted with an alkyl sulfinylene group. The unsubstituted alkylsulfinylalkyl group is, for example, 2 to 12 carbons.

The term "alkylsulfonylalkyl" as used herein, denotes an alkyl group, as defined herein, substituted with an alkylsulfonyl group. An unsubstituted alkylsulfonylalkyl group, such as from 2 to 12 carbons.

The term "alkynyl" as used herein, denotes a monovalent straight or branched chain group of from 2 to 6 carbon atoms including a carbon-carbon reference, such as ethynyl, 1-propynyl and the like.

The term "脒" as used herein, refers to a -C(=NH)NH ₂ group.

The term "amino" as used herein, denotes -NH ₂ group, or mono-NHR ^N1 , wherein R ^N1 can be an OH, NO ₂ , NH ₂ , NR ^N2 ₂ , SO ₂ OR ^N2 , SO ₂ R ^N2 , SOR ^N2 , and wherein R ^N2 can be H, an alkyl group, or an aryl group.

The term "aminoalkyl" as used herein, denotes an alkyl group, as defined herein, substituted with an amine group.

The term "aryl" as used herein, denotes a mono- or bicyclic carbocyclic ring system having one or two aromatic rings, for example, phenyl, naphthyl, 1,2-dihydronaphthyl, 1,2, 3,4-tetrahydronaphthyl, anthracenyl, indanyl, fluorenyl, etc., and may be optionally substituted with 1, 2, 3, 4 or 5 substituents, independently selected from the following groups: (1) an alkanoyl group of 1 to 6 carbon atoms; (2) an alkyl group of 1 to 6 carbon atoms; (3) an alkoxy group of 1 to 6 carbon atoms; (4) an alkoxy group An alkyl group, wherein the alkyl group and the alkylene group are independently 1 to 6 carbon atoms; (5) an alkyl sulfinylene group of 1 to 6 carbon atoms; (6) an alkyl sulfinyl alkane group a group wherein the alkyl group and the alkylene group are independently 1 to 6 carbon atoms; (7) an alkylsulfonyl group of 1 to 6 carbon atoms; (8) an alkylsulfonylalkyl group wherein the alkyl group And the alkylene group are independently 1 to 6 carbon atoms; (9) aryl; (10) amine group; (11) aminoalkyl group of 1 to 6 carbon atoms; (12) heteroaryl group (13) an alkaryl group in which an alkylene group is 1 to 6 carbon atoms; (14) an aryl fluorenyl group; (15) an azide group; (16) an azide alkyl group having 1 to 6 carbon atoms; (17) Formaldehyde (carbox aldehyde) (18) (formaldehyde) alkyl group, wherein the alkylene group is 1 to 6 carbon atoms; (19) a cycloalkyl group of 3 to 8 carbon atoms; (20) an alkylcycloalkyl group in which a cycloalkyl group a group of 3 to 8 carbon atoms, an alkylene group of 1 to 10 carbon atoms; (21) a halogen; (22) a halogen alkyl group of 1 to 6 carbon atoms; (23) a heterocyclic group; (24) (heterocyclyl)oxy; (25) (heterocyclic fluorenyl); (26) hydroxy; (27) hydroxyalkyl of 1 to 6 carbon atoms; (28) nitro; (29) 1 to 6 carbons a nitroalkyl group of an atom; (30) an N-protected amine group; (31) an N-protected aminoalkyl group, wherein the alkylene group is 1 to 6 carbon atoms; (32) an oxy group; 33) a sulfanyloxy group of 1 to 6 carbon atoms; (34) a thioalkoxyalkyl group, wherein the alkyl group and the alkylene group are independently 1 to 6 carbon atoms; (35)-(CH) ₂ ) _q CO ₂ R ^A , wherein q is an integer from 0 to 4, and R ^{A is} selected from the group consisting of (a) alkyl, (b) aryl and (c) alkylaryl, wherein the alkylene The group is 1 to 6 carbon atoms; (36)-(CH ₂ ) _q CONR ^B R ^C wherein q is an integer from 0 to 4 and wherein R ^B and R ^{C are} independently selected from the following group: (a) hydrogen, (b) alkyl, (c) aryl and (d) alkaryl, wherein , the alkylene group is 1 to 6 carbon atoms; (37)-(CH ₂ ) _q SO ₂ R ^D wherein q is an integer of 0 to 4, and R ^{D is} selected from the group consisting of the following (a) alkyl group, (b) an aryl group and (c) an alkaryl group, wherein the alkylene group is 1 to 6 carbon atoms; (38)-(CH ₂ ) _q SO ₂ NR ^E R ^F wherein q is an integer of 0 to 4 Wherein each of R ^E and R ^F is independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl and (d) alkaryl, wherein the alkylene group is 1 Up to 6 carbon atoms; (39)-(CH ₂ ) _q NR ^G R ^H , wherein q is an integer from 0 to 4, and each of R ^G and R ^H is independently selected from the group consisting of (a) hydrogen; (b) an N-protecting group; (c) an alkyl group of 1 to 6 carbon atoms; (d) an aliphatic alkenyl group of 2 to 6 carbon atoms; (e) an aliphatic alkynyl group of 2 to 6 carbon atoms; And arylalkyl; The cycloalkyl group is 3 to 8 carbon atoms, and the alkylene group is 1 to 10 carbon atoms, but no two groups are bonded to the nitrogen atom by a carbonyl group or a sulfonium group; (40) sulfur Alcohol; (41) perfluoroalkyl; (42) perfluoroalkoxy; (43) aryloxy (44) cycloalkoxy; (45) cycloalkylalkoxy; and (46) arylalkoxy.

The term "arylalkoxy" as used herein, denotes an alkaryl group which is bonded to the parent molecular group by an oxygen atom. An unsubstituted arylalkoxy group, for example, 7 to 16 carbons.

The term "aryloxy" denotes a chemical substituent -OR' wherein R' is an aryl group of 6 to 18 carbon unless otherwise specified.

The terms "aryloyl" and "aroyl" are used interchangeably herein to denote an aryl group bonded to a parent molecular group by a carbonyl group. An unsubstituted aryl group, such as 7 or 11 carbon.

The term "azido (azido)" represents a N ₃ group, which can be used represented by N = N = N.

The term "azidoalkyl" denotes an azide group bonded to a parent molecular group via an alkyl group.

The term "carbonyl" as used herein, denotes a C(O) group, and may be represented by C=O.

The term "carboxyaldehyde" stands for a CHO group.

The term "carboxaldehyde alkyl" denotes a formaldehyde group which is bonded to the parent molecular group via an alkylene group.

The term "cycloalkyl" as used herein, unless otherwise specified, represents a monovalent saturated or unsaturated, non-aromatic cyclic hydrocarbon radical of from 3 to 8 carbons, for example, cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, cycloheptyl, bicyclo [2.2.1.] heptyl and the like. The cycloalkyl group of the present invention may be optionally substituted with: (1) an alkane group of 1 to 6 carbon atoms; (2) an alkyl group of 1 to 6 carbon atoms; (3) 1 to 6 carbon atoms. Alkoxy group; (4) alkoxyalkyl group, wherein the alkyl group and the alkylene group are independently 1 to 6 carbon atoms; (5) an alkyl sulfinylene group of 1 to 6 carbon atoms (6) an alkylsulfinylalkyl group in which an alkyl group and an alkylene group are independently 1 to 6 carbon atoms; (7) an alkylsulfonyl group of 1 to 6 carbon atoms; (8) An alkylsulfonylalkyl group, wherein the alkyl group and the alkylene group are independently 1 to 6 carbon atoms; (9) an aryl group; (10) an amine group; (11) 1 to 6 carbon atoms An aminoalkyl group; (12) a heteroaryl group; (13) an alkylaryl group in which an alkylene group is 1 to 6 carbon atoms; (14) an aryl fluorenyl group; (15) an azide group; An azidoalkyl group of 1 to 6 carbon atoms; (17) formaldehyde; (18) a formaldehyde alkyl group in which an alkylene group is 1 to 6 carbon atoms; (19) a ring of 3 to 8 carbon atoms An alkyl group; (20) an alkylcycloalkyl group wherein the cycloalkyl group is 3 to 8 carbon atoms, the alkylene group is 1 to 10 carbon atoms; (21) halogen; (22) 1 to 6 carbon atoms Haloalkyl; (23) heterocyclic; (24) Epoxy group; (25) heterocyclic fluorenyl group; (26) hydroxy group; (27) hydroxyalkyl group of 1 to 6 carbon atoms; (28) nitro group; (29) nitroalkane of 1 to 6 carbon atoms (30) an N-protected amine group; (31) an N-protected aminoalkyl group, wherein the alkylene group is 1 to 6 carbon atoms; (32) an oxy group; (33) 1 to 6 a sulfanyloxy group of a carbon atom; (34) a thioalkoxyalkyl group, wherein the alkyl group and the alkylene group are independently 1 to 6 carbon atoms; (35)-(CH ₂ ) _q CO ₂ R ^A wherein q is an integer of 0 to 4, R & lt select the group ^A consisting of (a) alkyl, (b) aryl and (c) alkaryl, where the alkylene group is from 1 to 6 carbon atoms, (36)-(CH ₂ ) _q CONR ^B R ^C wherein q is an integer from 0 to 4, and R ^B and R ^{C are} independently selected from the group consisting of (a) hydrogen, (b) alkyl, ( c) an aryl group and (d) an alkylaryl group in which the alkylene group is 1 to 6 carbon atoms; (37)-(CH ₂ ) _q SO ₂ R ^D wherein q is an integer from 0 to 4, R ^{D is} selected Freely consisting of the following groups (a) alkyl, (b) aryl and (c) alkaryl wherein the alkylene group is from 1 to 6 carbon atoms; (38)-(CH ₂ ) _q SO ₂ NR ^E R ^F wherein q is an integer of 0 to 4, each of R ^E and R ^F is independently choose freely below To the group (a) hydrogen, (b) alkyl, (c) aryl and (d) alkaryl, where the alkylene group is from 1 to 6 carbon _{atoms; (39) - (CH 2} ) q NR ^G R ^H wherein q is an integer from 0 to 4, and each R ^G and R ^H are independently selected from the group consisting of (a) hydrogen; (b) N-protecting group; (c) 1 to 6 carbons An alkyl group of an atom; (d) an alkenyl group of 2 to 6 carbon atoms; (e) an alkynyl group of 2 to 6 carbon atoms; (f) an aryl group; (g) an alkylaryl group in which an alkylene group a cycloalkyl group of 1 to 6 carbon atoms; (h) 3 to 8 carbon atoms; and (i) an alkylcycloalkyl group wherein the cycloalkyl group is 3 to 8 carbon atoms and the alkylene group is 1 Up to 10 carbon atoms, but no two groups are bonded to the nitrogen atom via a carbonyl group or a sulfonyl group; (40) sulfur; (41) perfluoroalkyl; (42) perfluoroalkoxy; (43) An aryloxy group; (44) a cycloalkoxy group; (45) a cycloalkylalkoxy group; and (46) an arylalkoxy group.

The term "cycloalkyloxy" or "cycloalkoxy", as used interchangeably herein, denotes a cycloalkyl group, as defined herein, which is bonded to the parent molecular group via an oxygen atom. Unsubstituted cycloalkoxy groups such as 3 to 8 carbons.

As used herein, the term "effecive amount" or "sufficient amount" means that the amount is sufficient for beneficial or desired results, such as clinical outcomes, etc., "effective amount" depends on The context of its application. For example, in the context of an agent that administers an NOS inhibitor, an effective amount of the agent refers, for example, to a response obtained against the administration of the agent, an amount sufficient to achieve a reduction in NOS activity.

The term "halide" or "halogen" or "hal" or "halo" as used herein, denotes bromo, chloro, iodo or fluoro.

The term "heteroaryl" as used herein, denotes a sub-combination of heterocycles, as defined herein, which is aromatic, ie, which includes 4n+2 pi electrons in a mono- or polycyclic ring system.

The terms "heterocycle" or "heterocyclyl" are used interchangeably herein to denote a 5-, 6- or 7-membered ring, unless otherwise specified, including 1, 2, 3 or 4 heteroatoms. Independently choose the group of nitrogen, oxygen and sulfur. The 5-membered ring has 0 to 2 double bonds, and the 6- and 7-membered rings have 0 to 3 double bonds. The term "heterocycle" also includes bicyclic, tricyclic, and tetracyclic groups, wherein any of the foregoing heterocycles heals to 1, 2, or 3 rings, independently selected from the group consisting of aryl rings, cyclohexyl Alkane ring, cyclohexene, cyclopentane ring, cyclopentene ring, and other monocyclic heterocycles, such as fluorenyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuranyl, benzene And thiophene and so on. Heterocycle, such as pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, isopiperidine Base, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazole Alkyl, isothiazolyl, isothiazolidinyl, fluorenyl, quinolyl, isoquinolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, thiol, thiazolidine , isothiazolyl, isoxazolyl, triazolyl, tetrazolyl, oxadiazolyl, uryl, thiadiazolyl, pyrimidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiol, di Hydrothienyl, indanyl, tetrahydroquinolyl, tetrahydroisoquinolyl, pyranyl, dihydropyranyl, dithiazolyl, benzofuranyl, benzothiophene and the like. Heterocyclic groups also include compounds of the formula: , wherein F' is selected from the group consisting of -CH ₂ -, -CH ₂ O-, and -O-, and G' is selected from the group consisting of -C(O)- and -(C(R') (R")) _v - wherein each R' and R" is independently selected from the group consisting of hydrogen or an alkyl group of 1 to 4 carbon atoms, and v is 1 to 3, including a group: for example, 1 , 3-benzodioxanyl, 1,4-benzodioxanyl and the like. Any of the heterocyclic groups mentioned herein may be optionally substituted with 1, 2, 3, 4 or 5 substituents, independently selected from the group consisting of: (1) 1 to 6 carbon atoms. An alkyl group; (2) an alkyl group of 1 to 6 carbon atoms; (3) an alkoxy group of 1 to 6 carbon atoms; (4) an alkoxyalkyl group in which an alkyl group and an alkylene group are independently Ground, 1 to 6 carbon atoms; (5) alkyl sulfinylene group of 1 to 6 carbon atoms; (6) alkyl sulfinylalkyl group, wherein the alkyl group and the alkylene group are independently 1 to 6 carbon atoms; (7) alkylsulfonyl group of 1 to 6 carbon atoms; (8) alkylsulfonylalkyl group, wherein the alkyl group and the alkylene group are independently 1 to 6 a carbon atom; (9) an aryl group; (10) an amine group; (11) an aminoalkyl group of 1 to 6 carbon atoms; (12) a heteroaryl group; (13) an alkylaryl group in which an alkylene group is 1 to 6 carbon atoms; (14) aryl fluorenyl; (15) azide group; (16) azidoalkyl group of 1 to 6 carbon atoms; (17) formaldehyde; (18) formaldehyde alkyl group, wherein An alkylene group of 1 to 6 carbon atoms; (19) a cycloalkyl group of 3 to 8 carbon atoms; (20) an alkylcycloalkyl group wherein the cycloalkyl group is 3 to 8 carbon atoms, an alkylene group Group of 1 to 10 carbon atoms (21) halogen; (22) haloalkyl of 1 to 6 carbon atoms; (23) heterocyclic group; (24) heterocyclic oxy; (25) heterocyclic fluorenyl; (26) hydroxy; a hydroxyalkyl group of 1 to 6 carbon atoms; (28) a nitro group; (29) a nitroalkyl group of 1 to 6 carbon atoms; (30) an N-protected amine group; (31) an N-protected amine An alkyl group, wherein the alkylene group is 1 to 6 carbon atoms; (32) an oxy group; (33) a thioalkoxy group of 1 to 6 carbon atoms; (34) a thioalkoxyalkyl group, wherein The alkyl and alkylene groups are independently from 1 to 6 carbon atoms; (35)-(CH ₂ ) _q CO ₂ R ^A wherein q is an integer from 0 to 4, and R ^{A is} selected from the group consisting of: An alkyl group, (b) aryl group and (c) alkaryl group, wherein the alkylene group is 1 to 6 carbon atoms; (36)-(CH ₂ ) _q CONR ^B R ^C wherein q is 0 to 4 Integer, R ^B and R ^{C are} independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl and (d) alkaryl, wherein the alkylene group is from 1 to 6 Carbon atom; (37)-(CH ₂ ) _q SO ₂ R ^D wherein q is an integer from 0 to 4 and R ^{D is} selected from the group consisting of (a) alkyl, (b) aryl and (c) alkane An aryl group wherein the alkylene group is 1 to 6 carbon atoms; (38)-(CH ₂ ) _q SO ₂ NR ^E R ^F Wherein q is an integer from 0 to 4, and each of R ^E and R ^F is independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl, and (d) alkylaryl. The alkylene group is 1 to 6 carbon atoms; (39)-(CH ₂ ) _q NR ^G R ^H wherein q is an integer of 0 to 4 and each of R ^G and R ^H is independently selected from the following Group (a) hydrogen; (b) N-protecting group; (c) alkyl group of 1 to 6 carbon atoms; (d) aliphatic alkenyl group of 2 to 6 carbon atoms; (e) 2 to 6 carbon atoms An alkynyl group; (f) an aryl group; (g) an alkylaryl group wherein the alkylene group is 1 to 6 carbon atoms; (h) a cycloalkyl group of 3 to 8 carbon atoms; and (i) an alkane ring An alkyl group, wherein the cycloalkyl group is 3 to 8 carbon atoms, and the alkylene group is 1 to 10 carbon atoms, but no two groups are bonded to the nitrogen atom via a carbonyl group or a sulfonium group; a thiol; (41) a perfluoroalkyl group; (42) a perfluoroalkoxy group; (43) an aryloxy group; (44) a cycloalkoxy group; (45) a cycloalkyl alkoxy group; Arylalkoxy.

The terms "heterocyclyloxy" and "heterocyclooxy" are used interchangeably herein to denote a heterocyclic group, as defined herein, bonded to a parent molecular group via an oxygen atom.

The terms "heterocyclyloyl" and "heterocycle oyl" are used interchangeably herein to denote a heterocyclic group, as defined herein, bonded to a parent molecular group via a carbonyl group.

The term "hydroxy" or "hydroxyl" as used herein denotes an -OH group.

The term "hydroxyalkyl" as used herein, denotes an alkyl group, as defined herein, substituted by 1 to 3 hydroxyl groups, except that no more than one hydroxyl group may be bonded to a single carbon atom of the alkyl group. For example, hydroxymethyl, dihydroxypropyl, and the like.

The terms "inhibit" or "suppress" or "reduce" are used to refer to a condition or parameter of interest, when the same conditions are the same, or when compared to a condition, with respect to function or activity, For example, NOS activity, function or activity reduction.

The term "N-protected amine" as used herein, refers to an amine linkage as defined herein having an N-protected or nitrogen-protecting group as defined herein.

The terms "N-protecting group" and "nitrogen protecting group" as used herein mean that the group is intended to protect the amine group from undesired reactions during the synthesis step. Commonly used N- protecting groups are disclosed in Greene "Protective Groups In Organic Synthesis" 3 rd Edition (John Wiley & Sons, New York, 1999), incorporated herein by reference. The N-protecting group includes a mercapto group, an arylsulfonyl group or a methotrexate group, for example, a decyl group, an ethyl fluorenyl group, a propyl fluorenyl group, a trimethyl ethinyl group, a tert-butyl acetyl group, and 2- Chloroacetyl, 2-bromoethenyl, trifluoroethylidene, trichloroethane, phthalic acid, o-nitrophenoxyethyl, α-chlorobutyridyl, benzhydryl , 4-chlorobenzhydryl, 4-bromobenzylidene, 4-nitrobenzylidene and chiral auxiliary, such as protected or unprotected D, L or D, L-amino acids, For example: alanine, leucine, phenylalanine, etc.; sulfonate groups, for example: benzenesulfonyl, p-toluenesulfonyl, etc.; carbamate forming groups, such as benzyloxycarbonyl, P-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethyl Oxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4, 5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-diphenyl)-1-methylethoxycarbonyl, α,α-dimethyl 3-,5-dimethoxybenzyloxycarbonyl, benzylbenzyloxycarbonyl, tert-butoxycarbonyl, diisopropylmethoxycarbonyl, isopropoxycarbonyl, ethoxycarbonyl, methoxy Carbocarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyl An oxycarbonyl group, a gold steel alkyloxycarbonyl group, a cyclohexyloxycarbonyl group, a phenylthiocarbonyl group, etc., an arylalkyl group s such as a benzyl group, a triphenylmethyl group, a benzyloxymethyl group, etc., and a formyl group, For example: trimethylmethane alkyl and the like. Preferred N-protecting groups are: mercapto, ethenyl, benzhydryl, trimethylethenyl, tert-butylethenyl, alanine, phenylsulfonyl, benzyl, Third butoxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).

The term "nitro" as used herein, denotes a -NO ₂ group.

The term "oxo" is used herein to mean =O.

The term "perfluoroalkyl" as used herein, denotes an alkyl group as defined herein, wherein the hydrogen radicals each bonded to the alkyl group are substituted with a fluorine radical. Perfluoroalkyl groups are, for example, trifluoromethyl, pentafluoroethyl and the like.

The term "perfluoroalkoxy" as used herein, denotes an alkoxy group, as defined herein, wherein each hydrogen radical bonded to an alkoxy group is substituted with a fluororadical.

The term "pharmaceutically acceptable salts" as used herein means that the salts are medically judged to be suitable for contact with human and animal tissues without adverse toxicity, irritation, allergic reactions, etc., and are reasonably reasonable. Advantages / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. detail pharmaceutically acceptable salts in J. Pharmaceutical Sciences 66: 1-19, 1977. Such salts can be prepared in situ upon final isolation and purification of the compounds of the invention, or separately by reacting a free base group with a suitable organic acid. Representative acid addition salts, including: acetate, adipate, alginate, ascorbate, aspartate, besylate, benzoate, sodium hydrogen sulfate, borate, butyric acid Salt, camphorate salt, camphoric acid sulfonate, citrate, cyclopentane propionate, diglycolate, lauryl sulfate, ethane sulfonate, fumarate, glucoheptane Acid salt, glycerin phosphate, hemisulfate, heptanoate, hexanoate, hydrogen bromide, hydrogen chloride, hydrogen iodide, 2-hydroxy-ethane sulfonate, lactobionate, lactate, Laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinic acid, nitrate, oleate, oxalate , palmitic acid, pamoate, acid salt, persulphate, 3-phenylpropionate, phosphate, picrate, trimethylacetate, propionate, stearate, Succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate, and the like. Representative alkali or alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium and the like, and non-toxic ammonium, quaternary ammonium and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium , methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.

As used herein, the term "pharmaceutically acceptable pre-drug" means that the compound of the present invention is pre-drug-removed and is medically judged to be suitable for contact with human and animal tissues without adverse toxicity, irritation, allergic reaction, etc. And has a commensurate reasonable advantage/risk ratio and is effective for its intended use, as well as the zwitterionic form of the compounds of the invention, if possible.

The term "Ph" as used herein means phenyl.

The term "precursor" as used herein, denotes a compound which, in vivo , for example, hydrolyzes in the blood, rapidly converts to the parent compound of the above formula. The prodrug of the compound of the present invention may be a conventional ester. Some commonly used as the prodrug ester, phenyl ester, aliphatic (C ₈ -C ₂₄₎ esters, acyl oxymethyl esters, carbamates and amino acid esters. For example, a moiety of the compound of the invention comprising an OH group can be deuterated in its prodrug form. A more complete discussion can be found in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche. ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987 and Judkins et al ., Synthetic Communications 26(23): 4351-4367, 1996, each incorporated herein by reference.

The term "selectively inhibits nNOS" or "selective nNOS inhibitor" refers to a substance, such as a compound of the invention, in an in vitro assay, as described herein, as compared to eNOS and/or Or iNOS isomeric isomers that inhibit or bind to nNOS isoforms more effectively. Selective inhibition of ₅₀ available values IC, K _i inhibition of the reciprocal value or values represent percentages, when the material in which nNOS assay than in the eNOS and / or iNOS test was low. Preferably, IC ₅₀ or K _i value of less than 2-fold. More preferably, IC ₅₀ or K _i value is 5 times lower, 10, 50 or even 100 times.

The term "solvate" as used herein, refers to a compound of the invention wherein a suitable solvent molecule is included in its crystal lattice. A suitable solvent is physiologically tolerable at the dosage. Examples of suitable solvents are: ethanol, water, and the like. When water is a solvent, the molecule means "hydrate."

The term "spirocyclic" as used herein, denotes an alkylene diradical, which is bonded to the same carbon atom of the parent group at both ends to form a spiro group.

The term "sulfonyl" as used herein, refers to a -S(O) _2- group.

The term "thioalkylheterocyclyl" as used herein, denotes a thioalkoxy group substituted with a heterocyclic group.

The term "thioalkoxy" as used herein, denotes a monoalkyl group which is bonded to the parent molecular group via a sulfur atom. The unsubstituted alkylthio group is, for example, one to six carbons.

The term "thiol" represents a -SH group.

As used herein and as is well known in the art, "treatment" is a method used to obtain a beneficial or desired result, such as a clinical outcome. Benefits or desired results may include, but are not limited to, relieving or alleviating one or more symptoms or symptoms; narrowing the scope of the disease, disorder, or condition; stabilizing (ie, not worsening) the state of the disease, disorder, or condition; preventing the disease, Disorder or spread of symptoms; delay or slow down the progression of the disease, disorder, or symptoms; relieve or alleviate the disease, disorder, or symptoms; and relieve (partially or completely), detectable or undetectable. "Treatment" can also mean prolonged survival compared to the life expectancy of an untreated subject. "Palliating" disease, disorder or symptom, meaning the extent of the disease, disorder or symptom and/or the extent to which the clinical manifestation is not reduced and/or the time course of progression is slowed, or compared to when the treatment is not accepted, For the lengthened. This term also includes prophylactic treatment or prevention of the treatment of one or more syndromes or diseases, disorders or symptoms.

The present invention provides novel quinolone, tetrahydroquinoline, and related compounds having nitric oxide synthase (NOS) inhibitory activity, pharmaceutical and diagnostic compounds containing the same, and pharmaceutical uses thereof. Exemplary compounds of the invention are shown in Table 2.

Exemplary methods for synthesizing the compounds of the invention are as described herein.

Method of preparing a compound of the invention

The compounds of the present invention can be prepared by processes analogous to those established in the art of this invention, for example, as shown in Schemes 1-8.

The compound of formula 3, wherein R ¹ and Q as defined herein to be by alkylation under standard conditions, with a compound of formula 1 of formula 2 or a suitably protected derivative of, wherein R ^{1 is} as Definitions, except that R ^{1 is} not H, and "LG" is a leaving group such as chlorine, bromine, iodine, or a sulfonate such as methanesulfonate, tosylate, or triflate ( Triflate)). The alkylation conditions which affect the compound of formula 1 and the compound of formula 2 include, for example, heating the compound of formula 1 with a compound of formula 2 , with or without a solvent, optionally in the presence of a suitable base (see Scheme 1). Preferred conditions include, for example, heating the compounds of Formulas 1 and 2 in the presence of a solvent such as DMF, and potassium carbonate.

Scheme 1 - General Reaction Scheme for Preparation of Oxygen Aza (Oxaza) Compounds

The compound of formula 4 can be prepared by reduction of the nitro group of the compound of formula 3 or a suitably protected derivative by the standard conditions shown in Scheme 1. In one embodiment, standard reducing conditions include the use of Raney Nickel in a polar solvent such as methanol or ethanol at reflux temperature. Alternatively, a compound of formula 4 can be prepared by hydrogenating a compound of formula 3 using a suitable catalyst, such as palladium-carbon, in ethanol or other solvent or combination of solvents.

As shown in Scheme 1, a compound of formula 6 can be prepared by reacting a compound of formula 5 with a compound of formula 4 in accordance with procedures of the prior art (US 2006/0258721 A1).

Scheme 2 - General Reactions for the Preparation of Compounds with a Side Group of a Propylamine Group case. Or a compound of formula 3, wherein R ¹ is (CH ₂ ) _n X ¹ , wherein X ¹ is: , R ^1A , R ^1B , R ^1C , R ^1D , Y ¹ are CH ₂ , O, S, NR ¹ , N1, p1, and q1, as defined in the Examples herein, involving a compound of formula 7, wherein LG is a suitable a leaving group, such as chlorine, bromine, iodine or a sulfonate (eg, mesylate, tosylate, or triflate), reacted with a compound of formula 8, wherein X ^{1 is} as defined above, The standard alkylation conditions shown in Scheme 2. When LG is an aldehyde or ketone group, standard reducing amination conditions (Abdel-Majid et al. J. Org. Chem. 61: 3849-3862, 1996) may use suitable reducing agents such as NaBH ₄ , NaBH (OAc). _3. NaCNBH ₄ or the like in an alcoholic solvent such as ethanol to produce a compound of formula 9. The reductive amination can be carried out in one reaction, or a mixture of the compound of the formula 7 and the compound of the formula 8 can be obtained in situ to obtain the imine, which is then sequentially reduced with a suitable reducing agent. After the compound 9 was converted to the compound 11 by nitro reduction, it was amidated in a similar manner to that described in Scheme 1.

When alkylation produces a compound of formula 9, wherein R ^1A or R ^1B is H, a suitable protecting group such as a Boc group may be required prior to reduction of the nitro group. The protecting group can then be reduced under standard conditions (e.g., when using a Boc group, under acidic conditions) to yield a compound of the invention. Alternatively, when R ^1A and/or R ^1B are monomethyl, the compound of formula 9 can be treated with a demethylating agent, such as a chloroformate reagent such as phenyl chloroformate, chloromethyl chloroformate, and the like. After reduction and amidination, the protecting group can be removed by excision under standard conditions. A preferred protecting group is phenyl carbamate, and preferred deprotection conditions include reaction under basic conditions (e.g., sodium hydroxide) in a suitable solvent, such as water, in the presence of a cosolvent such as methanol or ethanol.

Scheme 3 - General Reaction Scheme for the Preparation of Reduced Compounds

The compound of the formula 12 is produced from a compound of the formula 4 by reduction of guanamine with lithium aluminum hydride in an aprotic solvent such as THF, ether or the like. Or compound of formula 12 using an appropriate reducing agent such as BH _3, such as THF in the reduction of a suitable aprotic solvent. These compounds are then converted to the compound of formula 13 by coupling with reagent 5 as described in Scheme 1.

Scheme 4 - Preparation of a General Reaction Scheme for Compounds Attached to Nitrogen Ring Groups

Compounds of formula 16 can be prepared from compounds of formula 14 and formula 15 under standard reductive amination conditions (Abdel-Majid et al. J. Org. Chem. 61: 3849-3862, 1996). The compound of formula 17 can be prepared by aromatic halogenation of a compound of formula 16 in accordance with established procedures (de la Mare, "Electrophilic Halogenation," Cambridge University Press, Cambridge (1976)). Preferably, the compound of formula 16 is reacted with N-bromosuccinimide under neutral conditions. a compound of formula 18 which may be present in a suitable amino equivalent such as benzophenone imine, LiN(SiMe ₃ ) ₂ , Ph ₃ SiNH ₂ , NaN(SiMe ₃ ) ₂ , or lithium decylamine Next, metal catalyzed amination is carried out to prepare, wherein X is chlorine, bromine or iodine (Wolfe, et al. J. Org. Chem. 65: 1158-1174, 2000), (Huang and Buchwald, Org. Lett. 3 (21): 3417-3419, 2001). Preferably, the halogen is bromine and a palladium (0) or palladium (II) catalyst is present. Examples of suitable metal catalysts include, for example, palladium catalysts coordinated to a suitable ligand. Suitable palladium catalysts include tris-dibenzylideneacetone dipalladium (Pd ₂ dba ₃ ) and palladium acetate (PdOAc ₂ ), preferably Pd ₂ dba ₃ . Suitable ligands for palladium can vary widely, including, for example, XantPhos, BINAP, DPEphos, dppf, dppb, DPPP, ( o -biphenyl)-P( t- Bu) ₂ , ( o -biphenyl)-P ( Cy) ₂ , P( _t- Bu)3, P(Cy) ₃ , and others (Huang and Buchwald, Org. Lett. 3(21): 3417-3419, 2001). Preferably, the ligand is P(t-Bu) ₃ . Pd-catalyzed amination is carried out in a suitable solvent such as THF, dioxane, toluene, xylene, DME, etc., between room temperature and reflux temperature. Conversion of compound 18 to 19 was carried out under the conditions of Scheme 1. Compounds wherein R = H can be prepared by cleaving the appropriate protecting group PG. Appropriate protecting group. A third butoxycarbonyl (Boc) group is included which can be cleaved under acidic conditions such as aqueous HCl and a selective cosolvent.

Scheme 5 - General Reaction Scheme for the Preparation of Quinolones with Ring Groups

A compound of the formula 21 wherein X can be chloro, bromo or iodo and R is as defined herein, which can be prepared by standard reductive amination conditions with a compound of formula 20 and a compound of formula 15 (Abdel-Majid et al. J .Org. Chem. 61: 3849-3862, 1996). The compound of the formula 23 can be prepared by alternately coupling an acrylate 22 with a compound of the formula 21 under a Heck reaction condition using a suitable palladium catalyst (Beletskaya and Cheprakov. Chem. Rev. 100: 3009-3066, 200). . A preferred halogen is iodine in the presence of a palladium (0) or palladium (II) catalyst. Suitable palladium catalysts include tris-dibenzylideneacetone dipalladium (Pd ₂ dba ₃ ) and palladium acetate (PdOAc ₂ ), preferably PdOAc ₂ . Suitable ligands for palladium can vary widely and can include, for example, ( o-tolyl ) ₃ P, XantPhos, BINAP, DPEphos, dppf, dppb, DPPP, ( o -biphenyl)-P( t -Bu) ₂ , ( o -biphenyl)-P(Cy) ₂ , P( _t -Bu) 3 , P(Cy) ₃ , and others.

Compounds of formula 24 can be prepared by hydrogenating a compound of formula 23 using a suitable catalyst, such as palladium-carbon, in ethanol or other solvent or combination of solvents. There are a number of different hydrogenation conditions which can be employed at a conversion of 23 to 24 (see Rylander, "Hydrogenation Methods," Academic Press, New York (1985), Chpt 2).

The compound of the formula 25 can be prepared by hydrolyzing the ester 24 under standard conditions, such as aqueous sodium hydroxide in methanol. Subsequent cyclization can be carried out by heating under acidic aqueous conditions (Ogawa et al J. Med. Chem. 36: 2011-2017, 1993) or by coupling with a dehydrating agent such as the previously reported EDCI (Grice) Et al Bioorg. Med. Chem. Lett. 16:2209-2212, 2006). Compounds of general structure 25 are nitrated under previously reported conditions (Devita et al. WO 03/045313) to give compounds of general structure 26. The transfer of a compound of general structure 26 to a compound of general structure 28 can be carried out in accordance with the procedure described in Scheme 1.

Scheme 6 - Preparation of oxindole general reaction scheme

Compounds of general structure 30 can be prepared from anilines such as 29 according to known procedures ( J. Med. Chem. 2004, 47 , 2973-2976). The nitration of compound 30 is in accordance with the procedure reported in International Publication No. WO 03/045313. After reduction of the nitro group, coupling with the amidine reagent was carried out in accordance with previously reported procedures (US 2006/0258721 A1).

Scheme 7 - General reaction scheme for the preparation of porphyrins.

A compound of the general structure 35, starting from 32, is reduced in two steps using LiAlH4, followed by the above described oxime coupling reaction (US 2006/0258721 A1).

Scheme 8 - General Reaction Scheme for the Preparation of Indolones

A compound of formula 40, starting from oxindole 36, is prepared according to Scheme 8. The compound of formula 37 is obtained by reacting 36 with a suitably protected ketone of formula 15 in the presence of a base such as ammonia, pyrrolidine or the like in a suitable solvent such as ethanol or methanol. Preferably, ammonia is refluxed with methanol. The compound of formula 38 can be carried out by reduction of the double bond and the nitro group under standard hydrogenation conditions such as Pd on carbon in a hydrogen atmosphere or other conditions such as transfer hydrogenation. The compound of formula 40 is obtained by conversion 39 as previously described and deprotected under standard conditions. A preferred protecting group is a Boc protecting group which is cleaved under acidic conditions, such as refluxing in a methanolic HCl solution.

In some cases, the above listed chemical agents may require modification, for example, the use of protecting groups to avoid reactive groups, such as side reactions caused by reactive groups that act as substituents. This can be achieved by conventional protecting groups as described in "Protective Groups in Organic Chemistry," McOmie, Ed., Plenum Press, 1973 and in Greene and Wuts, "Protective Groups in Organic Synthesis," John Wiley & Sons, 3 ^rd Edition, 1999.

The compounds of the present invention, as well as intermediates for the preparation of the compounds of the present invention, may employ conventional techniques including extraction, chromatography, distillation and recrystallization. Isolation and purification from its reaction mixture (if necessary).

Formation of the desired compound salt is achieved using standard techniques. For example, the neutral compound is acid treated in a suitable solvent and the salt formed is isolated by filtration, extraction, or any other suitable method.

The solvates which form the compounds of the invention will depend on the compound and the solvating agent. In general, the solvate is isolated by dissolving the compound in a suitable solvent and by cooling or adding an anti-solvent. The sol is usually dried or azeotroped at normal temperature.

The preparation of the optical isomer of the compound of the present invention can be carried out by reacting a suitable optically active starting material under reaction conditions which do not cause racemization. Alternatively, individual mirror image isomers may be separated by isolation using standard techniques such as fractional crystallization or chiral HPLC.

The radiolabeled compounds of the invention can be prepared using standard methods known in the art. For example, tritium can be hydrogenated with a suitable precursor as a compound of the invention using standard techniques such as the use of helium and a catalyst to introduce a compound of the invention. Or a compound of the invention containing radioactive iodine, from the corresponding trialkyltin (suitably trimethyltin) derivative, using standard iodination conditions such as [ ^125I ]sodium iodide in the presence of chloramine-T Prepared in a suitable solvent such as dimethylformamide. The trialkyltin compound may be from a corresponding non-radioactive halogen, preferably an iodine compound, using standard palladium-catalyzed stannilation conditions such as hexamethylditin in the presence of ruthenium (triphenylphosphine). Palladium (0) is prepared in a blunt solvent such as dioxane, and at an elevated temperature, preferably 50-100 °C.

Medical use

Features of the invention are the use of all of the compounds of the invention, including in therapeutic methods, alone or in combination with other therapeutic substances, in compositions for inhibiting NOS, such as nNOS activity, for use in diagnostic assays and for use as research tools.

The compounds of the present invention have useful NOS inhibitory activity and are therefore useful for treating or reducing the risk of a disease or condition that can be attenuated by reducing NOS activity. Such diseases or conditions include those who synthesize or over-synthesize nitric oxide as a causative agent.

In summary, the invention features a method of treating or reducing the risk of a disease or condition caused by NOS activity, comprising administering an effective amount of a compound of the invention to a cell or animal in need thereof. Such diseases or symptoms include, for example, migraine headaches (with and without aura), neuropathic pain, chronic tension headache (CTTH), migraine with tenderness, overuse of medication, headache, neuropathic pain, AIDS-related neuropathic pain, chronic pain, Post-stroke central pain (CPSP), drug-induced hyperalgesia and/or tenderness, such as opioid-induced hyperalgesia, triptan (5-HT1D/1B synergist)-induced hyperalgesia/tender pain, acute pain, chronic Pain, neuropathy of diabetes, trigeminal neuralgia, neuropathic pain caused by chemotherapy (eg Taxol, cis-Platin, Doxorubicin, etc.), bone cancer pain, chemical dependence or addiction, such as drug addiction, cocaine addiction , nicotine addiction, methamphetamine-induced neurotoxicity, alcohol tolerance, dependence or withdrawal, or morphine/opioid (opioid) tolerance, dependence, hyperalgesia or ring Disruption, CNS disorders, including but not limited to epilepsy, anxiety, depression (alone or combined), attention deficit hyperactivity disorder (ADHD), psychopathy (psychosis) or dementia, neurodegenerative diseases or nerve damage, such as acute spinal cord injury , AIDS-associated dementia, Parkinson's disease, Alzheimer's disease, ALS, Hunter's disease, multiple sclerosis, neurotoxicity or head trauma, blood Related symptoms such as stroke, CABG-related neurological damage, HCA, post-stroke pain, ventricular shock, reperfusion injury or vascular dementia, diabetic nephropathy, inflammatory disease such as osteoarthritis or Inflammation of the neurons, or gastrointestinal disorders, such as ileostomy-associated diarrhea, Dumping Syndrome, or visceral pain.

The following is a general discussion of the basis for linking NOS inhibition and certain of these symptoms.

Migraine with or without aura

Asciano Sobrero first observed a small amount of nitroglycerin, a NO release agent, in 1847, which caused severe headaches, which led to the hypoxic hypoxia hypothesis of migraine (Olesen et al., Cephalagia 15: 94-100, 1995). A serotonin-induced 5HT _1D/1B synergist, such as sumatriptan, is used in the clinical treatment of migraine, which is known to prevent cortical dissemination inhibition in lissencephalic and gyrencephalic during migraine attacks. Extensive release of NO. Indeed, according to the display in rats, sumatriptan artificially increases cortical NO levels after perfusion of nitroglycerin (Read et al, Brain Res. 847: 1-8, 1999; ibid , 870 (1-2): 44 -53, 2000). In a randomized, double-blind migraine clinical trial in humans, a single intravenous response to LN ^G methyl arginine hydrogen chloride (L-NMMA, an NOS inhibitor) was observed with a 67% response rate. This effect is not due to simple vasoconstriction, as this effect was not observed in the doppler that determines the velocity of the middle cerebral artery (Lassen et al, Lancet 349: 401-402. 1997). In the first open study using the NO-phagocytic scavenger cobalamin, it was observed that 53% of patients had a 50% reduction in the frequency of migraine attacks and a reduction in overall migraine duration (van der Kuy et al. , Cephalgia 22 (7): 513-519, 2002).

Migraine with tenderness

Clinical studies have shown that 75% of patients develop skin tenderness (exaggerated skin sensitivity) during migraine attacks, and their development during migraine is detrimental to anti-migraine effects of triptan 5HT _1B/1D synergist (Burstein et al. , Ann. Neurol. 47:614-624, 2000; Burstein et al., Brain. 123: 1703-1709, 2000). Early administration of triptan, such as sumatriptan, can end migraine pain, and late sumatriptan intervention can't end migraine pain or reverse the exaggerated skin sensitivity of already migraine migraine patients (Burstein et al., Ann .Neurol. DOI: 10.1002/ana.10785, 2003; Burstein and Jakubowski, Ann. Neurol. 55:27-36, 2004). Peripheral and central hypersensitivity is associated with clinical characterization of migraine. In migraine patients, beating occurs 5-20 minutes after the onset of headache, and skin tenderness begins between 20-120 minutes (Burstein et al., Brain , 123: 1703-1709, 2000). In rats, the peripheral hypersensitivity of the injury caused by the experimental meninges occurred within 5 to 20 minutes of administration of the inflammatory broth (IS) to the dura mater (Levy and Strassman, J. Physiol. , 538:483-493). , 2002), and trigeminal neuronal central hypersensitivity occurs within 20-120 minutes after IS administration (Burstein et al, J. Neurophysiol. 79: 964-982, 1998). Administration of anti-migraine triptans in early or late stages, such as sumatriptan, has a similar effect on the development of central hypersensitivity and has been demonstrated in rats (Burstein and Jakubowski, see above ). Thus, early but not advanced sumatriptan inhibits the long-term increase in IS-induced spontaneous activity seen in central trigeminovascular neurons (clinically related to migraine intensity). In addition, in rats, advanced sumatriptan intervention does not prevent periorbital skin, sensitivity to IS-induced neurons in mechanical stimulation, nor does it reduce the threshold for heat (mechanism with the eye socket area) Clinically relevant to patients with hot tenderness). Conversely, early Sumatriptan inhibited IS caused by thermal and mechanical allergies. After the central hypersensitivity, late sumatriptan intervention reverses the enlargement of the dural receiving area and increases the sensitivity to dural depression (clinically related to the worsening of painful beating due to excessive bending), and early Intervention will inhibit its development.

Previous studies of migraine compounds, such as sumatriptan (Kaube et al, Br . J. Pharmacol . 109: 788-792, 1993), zolmitriptan (Goadsby et al, Pain 67: 355-359, 1996), naratriptan (Goadsby, etc.) Human, Br. J. Pharmacol. , 328: 37-40, 1997), rizatriptan (Cumberbatch et al, Eur. J. Pharmacol. , 362: 43-46 . 1998) or L-471-604 (Cumberbatch et al, Br. J. Pharmacol. 126: 1478-1486, 1999) examined its effect on non-sensitive central trigeminovascular neurons (on normal conditions) and did not reflect its effect on migraine pathology. Although triptan is effective in terminating migraine beating in early or late stages, the peripheral effects of sumatriptan cannot be resolved in the late stage by allergic effects on trigeminal vascular neurons. The limitation of the triptan indicates that the use of a drug that can cause central hypersensitivity failure, such as a compound of the present invention, may improve the treatment of migraine pain.

According to the system, nitroglycerin increases the nNOS level of caucasus and c-Fos-immunoreactive neurons (markers of neuronal activation) in rats after 4 hours, indicating that NO may mediate trigeminal nerves. Meta-allergic (Pardutz et al, Neuroreport 11 (14): 3071-3075, 2000). In addition, L-NAME attenuates the Fos expression in the caudal nucleus (caudalis) during sustained (2 hours) electrical stimulation of the superior sagittal sinus (Hoskin et al . Neurosci. Lett. 266(3): 173 -6, 1999). Considering the ability of NOS inhibitors to defeat acute migraine attacks (Lassen et al, Cephalalgia 18(1): 27-32, 1998), the compounds of the invention alone or in combination with other anti-nociceptive agents represent a therapeutic tenderness An excellent candidate for therapeutic agents for migraine patients.

Chronic headache (CTTH)

NO contributes to peripheral sensations (Aley et al., J. Neurosci. 1: 7008-7014, 1998) and the central nervous system (Meller and Gebhart, Pain 52: 127-136, 1993). Substantial experimental evidence suggests that neuronal stimulation in the CNS is increased by central hypersensitivity and long-term sensation of peripheral input, and that it is associated with increased NOS activation and NO synthesis (Bendtsen, Cephalagia 20: 486-508, 2000). ; Woolf and Salter, Science 288: 1765-1769, 2000). According to the show, experimental perfusion of NO providers, nitroglycerin, can cause headaches in patients. In a double-blind trial, patients with chronic tension-type headaches experienced a significant reduction in the intensity of headaches when receiving L-NMMA (an NOS inhibitor) (Ashina and Bendtsen, J. Headachne Pain 2: 21-24, 2001) Ashina et al., Lancet 243 (9149): 287-9, 1999). Therefore, the NOS inhibitor of the present invention may be useful for treating chronic tension-type headache.

Acute spinal cord injury, chronic or neuropathic pain

In humans, intradermal injection of NO causes pain (Holthusen and Arndt, Neurosci. Lett . 165: 71-74, 1994), thus showing that NO is directly related to pain. Furthermore, NOS inhibitors have little or no effect on the transmission of nociceptive effects in normal conditions (Meller and Gebhart, Pain 52: 127-136, 1993). NO involves the transmission of nociceptive data at the peripheral, spinal, and superspinal levels (Duarte et al, Eur. J. Pharmacol. 217: 225-227, 1992; Haley et al, Neuroscience 31: 251-258, 1992). Lesions or dysfunctions in the CNS may cause chronic pain symptoms known as central pain and include spontaneous pain, hyperalgesia, and mechanical and cold tenderness (Pagni, Textbook of Pain , Churchill Livingstone, Edinburgh, 1989, pp. 634-655; Tasker In: The Management of Pain , pp. 264-283, JJ Bonica (Ed.), Leaand Febiger, Philadelphia, PA, 1990; Casey, Pain and Central Nuerosystem Disease: The Central Pain Syndromes, pp .1-11 KLCasey (Ed.), Raven Press, New York, 1991). Systemic administration of (ip) NOS inhibitors 7-NI and L-NAME in rats with spinal cord injury has been shown to relieve chronic tenderness symptoms (Hao and Xu, Pain 66:313-319, 1996). The effect of 7-NI is not associated with a significant sedative effect and can be reversed by L-arginine (NO precursor). It is believed that hyperalgesia, which is maintained by heat, is mediated by nitric oxide, one of the spinal cords of the lumbar spine, and is administered by the spinal cord with nitric oxide synthase inhibitors such as L-NAME or soluble guanylate cyclase. Blocked by the inhibitor methylene blue ( Neuroscience 50(1): 7-10, 1992). Thus, the NOS inhibitors of the invention may be useful for the treatment of chronic or neuropathic pain.

Neuropathy of diabetes

The endogenous polyamine metabolite agmatine is a metabolite of arginine, which is also an NOS inhibitor and an N-methyl-D-aspartate (NMDA) channel antagonist. Streptozotocin for the neuropathic neuropathy of the neuropathic pain and Streptozotocin for neuropathic pain (Karadag et al, Neurosci, Lett. 339 (1): 88-90, 2003) effective. Therefore, a compound having NOS inhibitory activity, for example, a compound of the formula I, and a NOS inhibitor and an NMDA antagonist can effectively treat diabetic neuropathy and other neuropathic pain symptoms.

Inflammatory diseases and neuroinflammation

LPS, a well-known pharmacological tool, when injected intravenously, causes inflammation in many tissues and activates NFkappaB in all brain regions. When it is injected locally twill body, it activates the original inflammatory genes (Stern et al., J.Neuroimmunology, 109: 245-260,2000). Recently, it has been shown that NMDA receptor antagonist MK801 and brain selective nNOS inhibitor 7-NI all reduce the activation of NFkappaB in the brain, thus showing a clear role for glutamate and NO pathway in neuroinflammation (Glezer et al. , Neuropharmacology 45(8): 1120-1129, 2003). Thus, administration of a compound of the invention, alone or in combination with an NMDA antagonist, is effective in treating diseases due to neuroinflammation.

Stroke and reperfusion injury

The role of NO in ischemic brain damage can be protective or destructive, depending on the stage of the ischemic process and the cell spacing at which NO is produced (Dalkara et al, Brain Pathology 4:49, 1994). However, NO produced by eNOS is also beneficial by activating vasodilators to improve blood flow to the affected area (Huang et al., J. Cereb . Blood Flow Metab. 16:981, 1996). NO produced by nNOS contributes to the initial ischemic penumbra and causes greater infarction (Hara et al., J. Cereb. Blood Flow Metab. 16:605, 1996). Metabolic disorders due to reperfusion during and after ischemia can cause the expression and release of several cytokines that activate iNOS in some cellular forms, including certain central nervous systems. NO may be produced by iNOS at the cytotoxic level, and increased levels of iNOS contribute to progressive penumbra tissue damage, leading to larger infarcts (Parmentier et al, Br. J. Pharmacol. 127:546, 1999). Inhibition of i-NOS has been shown to alleviate ischemic brain damage in rats ( Am., J. Physiol. 268: R286, 1995).

According to the results, a combined neuroprotective effect was observed in the combined brain NMDA antagonists (eg MK-801 or LY293558) and nNOS selective inhibitors (7-NI or ARL17477) in the overall brain ischemia (Hicks) Et al., Eur. J. Pharmacol. 381: 113-119, 1999). Thus, administration of a compound of the invention alone, or in combination with an NMDA antagonist or a compound having mixed nNOS/NMDA activity, may be effective in treating symptoms of stroke and other neurodegenerative disorders.

Complications due to coronary bypass surgery

Cerebral damage and cognitive dysfunction remain the primary complication of patients undergoing coronary artery bypass surgery (CABG) (Roch et al, N. Eng. J. Med. 335: 1857-1864, 1996 ; Shaw et al, QJ Med. 58) :59-68, 1986). Brain damage after surgery is the result of pre-operational microembolism-induced ischemia. In a clinical trial of a random NMDA antagonist Remacemide, patients showed a reduced deficit and a significant improvement in overall postoperative learning ability (Arrowsmith et al, Stroke 29: 2357-2362, 1998). Due to the excessive release of excitotoxicity caused by glutamate and calcium, it is hoped that neuroprotective agents, such as the compounds of the invention or NMDA antagonists, alone or in combination, will improve the neurological consequences of CABG. Has a beneficial effect.

AIDS-associated dementia

HIV-1 infection can cause dementia. The HIV-1 coated protein gp-120 kills neurons in primary cortical cultures at low picoM levels and absorbs external glutamate and calcium (Dawson et al., Proc. Natl. Acad. Sci. USA 90 ( 8): 3256-3259, 1993). Its toxicity can be attenuated by administering the compound of the invention alone or in combination with other therapeutic agents such as NMDA antagonists (as described above).

NMDA antagonists useful in combination with the present invention include, for example: aptiganel; besonprodil; budipine; conantokin G; deletemine; dexanabinol; felbamate; fluorofelbamate; gacyclidine; glycine; ipenoxazone; kaitocephalin; lanicemine; licostinel; midafotel; milnacipran; neramexane; orphenadrine; Remacemide;topiramate;(alpha R )-alpha-amino-5-chloro-1-(phosphinomethyl)-1H-benzimidazole-2-propionic acid; 1-aminocyclopentane-carboxylic acid; -(Aminomethyl)-2-[[[(5 S )-9-chloro-2,3,6,7-tetrahydro-2,3-dioxo-1H-,5H-pyrido[1, 2,3-de]quinoxalin-5-yl]ethenyl]amino]phenoxy]-acetic acid; alpha-amino-2-(2-phosphoethyl)-cyclohexanepropionic acid; alpha -amino-4-(phosphinomethyl)-phenylacetic acid; (3E)-2-amino-4-(phosphinomethyl)-3-heptanoic acid; 3-[(1E)-2-carboxy-2- Phenylvinyl]-4,6-dichloro-1H-indole-2-carboxylic acid; 8-chloro-2,3-dihydropyridazine [4,5-b]quinoline-1,4- Diketone 5-oxide salt and 2-hydroxy-N,N,N-trimethyl-ethylammonium; N'-[2-chloro-5-(methylthio)phenyl]-N-methyl-N -[3-(methylthio)phenyl]-indole; N'-[2-chloro-5-(methylthio)phenyl]-N-methyl-N-[3-[( R )-A Kea sulfur Phenyl]-phenyl]- 6-chloro-2,3,4,9-tetrahydro-9-methyl-2,3-dioxo-1H-indolo[1,2-b]pyrazine-9 - acetic acid; 7-chlorosulfuric uric acid; (3 S , 4a R , 6 S , 8a R )-decahydro-6-(phosphinomethyl)-3-isoquinolinecarboxylic acid; (-)-6,7 -dichloro-1,4-dihydro-5-[3-(methoxymethyl)-5-(3-pyridyl)-4-H-1,2,4-triazol-4-yl] -2,3-quinoxalinedione; 4,6-dichloro-3-[(E)-(2-oxy-1-phenyl-3-pyrrolidinium)methyl]-1H-indole 2-carboxylic acid; (2 R , 4 S )-rel-5,7-dichloro-1,2,3,4-tetrahydro-4-[[(phenylamino)carbonyl]amino]- 2-quinolinecarboxylic acid; (3 R , 4 S )-rel-3,4-dihydro-3-[4-hydroxy-4-(phenylmethyl)-1-piperidinyl-]-2H- 1-benzopyran-4,7-diol; 2-[(2,3-dihydro-1H-indol-2-yl)amino]-acetamide; 1,4-dihydro-6- Methyl-5-[(methylamino)methyl]-7-nitro-2,3-quinoxalinedione; [2-(8,9-dioxo-2,6-diazadicarboxy) Cyclo [5.2.0] 壬-1(7)-en-2-yl)ethyl]-phosphonic acid; (2 R , 6 S )-1,2,3,4,5,6-hexahydro-3 -[(2S)-2-methoxypropyl]-6,11,11-trimethyl-2,6-methanol-3-benzole-9-ol; 2-hydroxy-5-[[ (pentafluorophenyl)methyl]amino]-benzoic acid; 1-[2-(4-hydroxyphenoxy)ethyl]-4-[(4-methylphenyl)methyl]-4- Piperidinol 1-[4-(1H-imidazol-4-yl)-3-butyne]-4-(phenylmethyl)-piperidine; 2-methyl-6-(phenylacetylene)-pyridine; 3- (phosphinomethyl)-L-phenylalanine; and 3,6,7-tetrahydro-2,3-dioxy-N-phenyl-1H,5H-pyrido[1,2,3-de] Quinoxaline-5-acetamide or as described in U.S. Patent Nos. 6,071,966; 6,034,134; and 5,061,703.

Cardiac shock

Cardiac shock (CS) is the leading cause of death in patients with acute myocardial infarction, with both increased NO and inflammatory cytokines. High levels of NO and peroxynitrite have many effects, including direct inhibition of cardiac contraction, inhibition of myocardial glandular respiration, alteration of glucose metabolism, reduction of phenolamine responsiveness, and induction of systemic vasodilation (Hochman, Circulation 107) : 2998, 2003). In a clinical study of 11 patients with persistent shock, administration of the NOS inhibitor L-NMMA increased urine output and blood pressure, and survival increased by 72% to 30 days (Cotter et al., Circulation 101:1258-1361, 2000). . In a randomized trial of 30 patients, L-NAME reportedly reduced patient mortality from 67% to 27% (Cotter et al., Eur. Heart. J. 24(14): 1287-95m 2003). Likewise, administration of a compound of the invention alone or in combination with other therapeutic agents may be useful in the treatment of cardiac shock.

Anxiety and depression

Recent studies on rats and mice in the forced swimming test (FST) have shown that NOS inhibitors have antidepressant activity in mice (Harkin et al, Eur. J. Pharm . 372: 207-213, 1999), and its role is mediated by a serotonin-dependent mechanism (Harkin et al., Neuropharmacology 44(5): 616-623, 1993). 7-NI demonstrates that the rat plus-maze test has an anti-anxiety activity (Yildiz et al, Pharmacology, Biochemistry and Behavior 65: 199-202, 2000), whereas the selective nNOS inhibitor TRIM has an FST pattern for depression and anxiety. The shading test is effective (Volke et al., Behavioral Brain Research 140 (1-2): 141-7, 2003). Administration of a compound of the invention to a afflicted individual, alone or in combination with other therapeutic agents, such as an antidepressant, may be useful for treating anxiety or depression.

Highly active attention deficit disorders (Attention Deficit Hyperactivity Disorder)

Spontaneous hypertension (SHR) rats and NaCl low excitability (NHE) rats with environmentally stimulating non-selective attention (NSA) were used as animal models of attention deficit hyperactivity disorder (ADHD) (Aspide et al. Behav. Brain Res. 95 (1): 23-33, 1998). Animals with such genetic variants showed an increase in episodes of rearing compared to normal animals, which had a shorter duration. A single injection of L-NAME 10 mg/kg resulted in an increased duration of parenting. Similarly, the use of more neuronal selective 7-NINA resulted in an increase in duration of maintenance after rapid (ip) administration, while a slow release of a single dose or a slow multiple release dose (sc in DMSO) would have the opposite effect. . Therefore, administration of a compound of the invention may be useful for the treatment of ADHD.

Psychosis (psychosis)

Phencyclidine (PCP) is a non-competitive NMDA channel blocker that produces behavioral side effects in humans and mammals, consistent with those observed in psychopathic patients. In two animal models of psychopathy, the nNOS selective inhibitor AR-R17477 inhibits PCP-induced hyperlocomotion and PCP-induced loss in prepulse inhibition of auditory response (Johansson et al. Pharmacol. Toxicol . 84(5): 226-33, 1999). These results suggest that nNOS is associated with psychopathy. Thus, administration of a compound of the invention to a afflicted individual may be useful in treating this or related disease or disorder.

Head trauma

The mechanism of neurological damage in patients with head trauma is similar to stroke and is associated with excessive glutamate release, hyperexcitatory calcium influx, oxidative stress and free radicals produced by granulocyte dysfunction and inflammation ( Drug & Market) Development 9 (3): 60-63, 1998). Treatment of animal nitric oxide synthase inhibitors, such as 7-NI and 3-bromo-7-nitrocarbazole, has been shown to improve neurological deficits in experimental traumatic brain injury (TBI) (Mesenge et al., J .Neurotrauma 13:209-14, 1996). Administration of a compound of the invention to a afflicted individual may be useful for treating neurological damage to the head wound.

Hypothermic Cardiac Arrest

Hypothermia cardiac arrest (HCA) is a technique used to protect against cardiac damage during cardiac surgery because the brain is susceptible to damage during blood flow intervention. Various neuroprotective agents have been used as modulators during HCA, and it has been predicted that a decrease in nitric oxide during HCA will improve neurological function. This is based on previous studies that glutamate excitotoxicity has a role in HCA-induced neurological damage (Redmond et al, J. Thorac. Cardiovasc. Surg. 107: 776-87, 1994; Redmond et al. Ann. Thorac. Surg. 59: 579-84, 1995) and NO regulate glutamate hyperexcitotoxicity (Dawson and Snyder, J. Neurosci. 14: 5147-59, 1994). In a study of 32 dogs, during a 2-hour HCA at 18 °C, neuronal NOS inhibitors were shown to reduce NO production in the brain, significantly reducing neuronal necrosis, and compared to the control group. Preferred neurological function (Tseng et al, Ann. Thorac. Surg. 67: 65-71, 1999). Administration of a compound of the invention may be useful to protect a patient from ischemic damage in cardiac surgery.

Neurotoxicity and neurodegenerative diseases

Granulocyte dysfunction, glutamate hyperexcitation toxicity, and oxidative damage caused by free radicals have been shown to be associated with many of the following neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Parkinson's disease. Parkinson's disease (PD), Alzheimer's disease (AD), and Hunter's disease (HD) (Schulz et al, Mol. Cell. Biochem . 174 (1-2): 193 -197, 1997; Beal, Ann. Neurol. 38: 357-366, 1995), and NO is the major regulator of these mechanisms. For example, Dawson et al ., Proc. Natl. Acad. Sci. USA 88(14): 6368-6371, 1991 report that NOS inhibitors such as 7-NI and L-NAME inhibit N-methyl-D-aspartate Neurotoxicity caused by neurotoxicity and other amino acid irritations.

(a) Parkinson’s disease

Studies have shown that NO plays an important role in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity, a commonly used Parkinson's disease animal model ( Matthews et al, Neurobiology of Disease 4: 114-121, 1997). MPTP is converted to MPP+ by MAO-B and rapidly transported from the dopamine transporter to the granulocytes of dopamine-containing neurons, followed by activation of nNOS, resulting in neuronal death. Mutant mice lacking the nNOS gene but having the eNOS gene reduced necrosis of substantia nigra after injection of MPP+ into the twill. In the study of primates, 7-NI exerts a clear neuroprotective and anti-Parkinson effect after the MPTP test (Hantraye et al. Nature Med. 2:1017-1021, 1996), as a non-specific inhibitor L-NAME (TSSmith et. al. Neuromorport 1994, 5, 2598-2600). These results indicate that administration of an appropriate dose of an NOS inhibitor, such as a compound of the invention, may be beneficial for the treatment of Parkinson's disease.

(b) Alzheimer’s Disease (AD)

The pathogenic system of AD is associated with infiltration of activated microglia and beta-like amyloid plaques of astrocyte. When cultured rat microglia are exposed to beta-type starch, especially in the presence of gamma-interferon, microglia have significant nitric oxide release (Goodwin et al., Brain Research 692 (1- 2): 207-14, 1995). Cultures of cortical neurons, treated with nitric oxide synthase inhibitors, provide neuroprotection due to toxicity induced by human beta-like starch (Resink et al, Neurosci. Abstr . 21:1010, 1995). Consistent with the glutamate hyperexciitation toxicity hypothesis of neurodegenerative disorders, the weak NMDA antagonist amantadine increases the life expectancy of PD patients (Uitti et al, Neurology 46(6): 1551-6, 1996). ). In a preliminary, placebo-controlled study of patients with vascular or Alzheimer's-type dementia, the NMDA antagonist memantine was associated with improved overall clinical impression and behavioral scores for geriatric scores. Sex (Winblad and Poritis, Int. J. Geriatr. Psychiatry 14: 135-46, 1999). These results indicate that administration of an appropriate dose of an NOS inhibitor, such as a compound of the invention, may be beneficial for the treatment of AD.

(c) amyotrophic lateral sclerosis (ALS)

Amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease characterized by selective motor neuron death. Cumulative evidence suggests that the pathogenic glutamate transporter of ALS did not adequately remove glutamate and that the distribution of Ca ²⁺ -permeable AMPA receptors in spinal motor neurons resulted in the display of glutamate - Caused by neurotoxicity. It has been found that ALS patients are in the spinal cord (Sasaki et al., Acta Neuropathol. (Berl) 101(4): 351-7, 2001) and glial cells (Anneser et al., Exp. Neurol. 171(2): 418-21 , 2001) increased nNOS immunoreactivity, suggesting that NO is an important factor in the pathogenesis of ALS. These results indicate that administration of an appropriate dose of an NOS inhibitor, such as a compound of the invention, may be beneficial for the treatment of ALS.

(d) Hunter's disease

The pathogenesis of Hunter's disease (HD) is a cause of excessive NO in all of the above reasons due to mutations in the Htt protein associated with excessive excitotoxicity, oxidative stress, and cellular dying (Peterson et al., Exp. Neurol. 157:1-18, 1999). Oxidative damage is a major consequence of a loss of energy metabolism and is present in the HD mode of injection of excitotoxic and granulosa inhibitors (A. Petersen et al, Exp. Neurol. 157: 1-18, 1999). This granular glandular dysfunction is associated with selective and progressive neuronal loss in HD (Brown et al, Ann. Neurol. 41:646-653, 1997). NO can directly damage the granular gland respiratory chain complex IV (Calabrese et al., Neurochem. Res . 25: 1215-41, 2000). Striatal medium spiny neuron has been shown to be a major target for the development of motor dysfunction in HD. Hyperphosphorylation and activation of NMDA receptors in these neurons may be involved in the development of motor dysfunction. It has been reported that the NMDA antagonist amantadine can improve the choreiform dyskinesias of HD (Verhagen Metman et al., Neurology 59: 694-699, 2002). Due to the role of nNOS in NMDA vector neurotoxicity, we expect that nNOS inhibitors, especially those that mix nNOS/NMDA or that combine nNOS and NMDA activity, can be alleviated or effective for HD. Pretreatment with 7-nitrocarbazole in rats can alleviate tibial necrosis due to stereotactic injection of malonate, which can cause symptoms similar to Hunter's disease (Hobbs et al., Ann. Rev. Pharm.Tox. 39:191-220, 1999). In a HD transgenic mouse model showing R6/1 of human mutant htt exonl (a 116 CAG repeat), mice at 11, 19, and 35 weeks showed normal peroxidase (SOD) fluid over 11 weeks. There is a progressive increase in oxidation, similar to wild-type (WT) mice; at 19 weeks, more than in WT mice and corresponding to the early course of disease; finally, at 35 weeks lower than in WT mice Residents (Pérez-Sevriano et al., Brain Res. 951: 36-42, 2002). The increased SOD activity contributes to the compensatory neuroprotective mechanism, and the 35-week reduction level corresponds to the failure protection mechanism. Accompanied by SOD levels, the level of calcium-dependent NOS was comparable to that of R6/1 mice in 11 weeks of mice, but increased significantly at 19 weeks and significantly decreased at 35 weeks compared to WT-controlled mice. . The level of nNOS performance was also significantly increased at 19 weeks relative to the control group, but significantly decreased at 35 weeks relative to the control group. No significant level changes were observed in eNOS performance and iNOS protein could not be detected during the course of the disease. Measurements of the course phenotype, such as increased weight loss, foot clasping behavior, and horizontal and vertical movement, are consistent with changes in NOS activity and nNOS performance. Finally, the results of administration of L-NAME to the R6/2 gene-transferred HD and WT mice showed that at 10 mg/kg, the tight-fitting behavior was improved to be similar to the control group, but at the highest dose of 500 mg/kg. Time-varying (Deckel et al., Brain Res. 919(1): 70-81, 2001). In HD mice, the increase in body weight gain was also significant at the 10 mg/kg dose, but decreased at the highest dose level of L-NAME relative to the control group. These results demonstrate that administration of a suitable dose of an NOS inhibitor, such as a compound of the invention, may be beneficial for the treatment of HD.

(e) Multiple sclerosis (MS)

MS is an inflammatory CNS myelin deprivation disease associated with cytokines and other inflammatory mediators. Many studies have shown that NO and its reactive derivative, peroxynitrite, are involved in the pathogenesis of MS (Acar et al . J. Neurol. 250(5): 588-92, 2003; Calabrese et al., Neurochem. Res . 28 (9). ): 1321-8, 2003). In an experimental autoimmune encephalomyelitis (EAE), an MS model, the level of nNOS in the spinal cord of EAE rats increased slightly, and treatment with 7-nitrocarbazole significantly delayed the onset of EAE paralysis. (Shin, J. Vet. Sci. 2 (3): 195-9, 2001). These results demonstrate that administration of a suitable dose of an NOS inhibitor, such as a compound of the invention, may be beneficial for the treatment of MS.

(f) Methamphetamine-induced neurotoxicity

Methyl amphetamine is neurotoxic by destroying dopamine nerve endings in vivo, according to the display, in vitro (Sheng et al., Ann. NY Acad. Sci. 801: 174-186, 1996) and in vivo (Itzhak et al., Neuroreport 11). (13): 2943-6, 2000) Animal models, methamphetamine-induced neurotoxicity can be alleviated by treatment with NOS inhibitors. Similarly, the nNOS selective inhibitor AR-17477AR, when administered to mice at 5 mg/kg sc, inhibits the loss of neurofibrillary protein NF68 induced by methamphetamine in the brain and inhibits the loss of twill dopamine and homovanillic acid (HVA). (Sanchez et al., J. Neurochem. 85(2): 515-524, 2003). These results demonstrate that administration of a suitable dose of an NOS inhibitor, such as a compound of the invention, may be beneficial for the treatment of neurotoxicity caused by methamphetamine.

Administration of a compound of the invention alone or in combination with other therapeutic agents, such as an NMDA antagonist, may be useful in protecting or treating any of the above neurodegenerative diseases. Furthermore, the compounds of the invention can be tested in standard tests for neuroprotection (see, for example, Am. J. Physiol. 268: R286, 1995).

Chemical dependence and drug addiction (eg, dependence on drugs, alcohol, and nicotine)

A key step in drug-induced response and dependence is the regulation of dopamine release from mesobilibic dopamine-producing neurons. Chronic administration of cocaine alters the critical control of dopamine at the level of synapses and the performance of proteins in the dopamine transporter (DAT).

(a) Cocaine addiction

Studies have shown that animals rely on intravenous self-administered stimulants, and dopamine is critical for their intensive stimulation. Recently, NO-containing neurons have been shown to be distributed along with the ventral tegmental area and dopamine, and NO regulates the release of dopamine (DA) caused by stimulators. Administration of a dopamine D1 receptor antagonist reduces the straital NADPH-diaphorase, a marker of NOS activity, and the D2 antagonist produces the opposite effect. L-arginine of NOS is also a promising DA regulator. Moreover, in vitro and in vivo, various NO-producing agents increase DA efflux or inhibit recovery. L-NAME has been shown to reduce the amount of self-administration and increase the interaction time of successive cocaine bases to significantly alter the coagulation of cocaine (Pudiak and Bozarth, Soc.Neurosci.Abs. 22:703 , 1996). This shows that NOS inhibition by the present invention may be useful for treating cocaine addiction.

(b) Tolerance and withdrawal symptoms caused by morphine/opioid

There is ample evidence supporting the opioid-dependent role of NMDA and NO pathways in animal adults and larvae. Rodent adult or neonatal bodies injected with morphine sulfate produce behavioral withdrawal after precipitation with naltrexone. The initial withdrawal symptoms of naltrexone can be reduced by administration of an NOS inhibitor, such as 7-NI or L-NAME (Zhu and Barr, Psychopharmacology 150(3): 325-336, 2000). In a related study, it has been shown that more nNOS selective inhibitor 7-NI reduces more morphine-induced withdrawal symptoms, including mastication, salivation, than less selective compounds. And reproductive effects (Vaupel et al, Psychopharmacology (Berl.) 118 (4): 361-8, 1995). This shows that NOS inhibition of the compounds of the invention may be useful in the treatment of morphine/opioid tolerance and withdrawal symptoms.

(c) Ethanol tolerance and dependence

Among the effects on ethanol dependence, the effect on ethanol tolerance is important as it promotes exaggerated drinking of alcoholic beverages (Lê and Kiianmaa, Psychopharmacology (Berl.) 94:479-483, 1988). In a rat ethanol tolerance study, rats with rapid motor incoordination and hypothermia were able to be administered by icv 7-NI without blocking brain ethanol concentration (Wazlawik and Morato, Brain Res. Bull. 57(2): 165-70, 2002). In other studies, NOS was inhibited by L-NAME (Rezvani et al, Pharmacol. Biochem . Behav . 50: 265-270, 1995) or by icv. Injection of antisense nNOS (Naassila et al, Pharmacol. Biochem . Behav . 67: 629-36, 2000) reduced ethanol consumption in these animals. This shows that NOS inhibition of the compounds of the invention may be useful in treating ethanol tolerance and dependence.

Administration of a compound of the invention, alone or in combination with other therapeutic agents, such as NMDA antagonists, may be useful for the treatment of chemical dependence and drug addiction.

Epilepsy

Administration of 7-NI with certain anti-epileptic agents, such as with carbamazepine, is shown in rats to have a protective effect against amygdala-kindled acute episodes without altering the concentration of roto-rod performance (Borowicz Et al., Epilepsia 41 (9: 112-8, 2000). Thus, administration of an NOS inhibitor, such as a compound of the invention, alone or in combination with other therapeutic agents, such as anti-epileptic drugs, may be useful for treating epilepsy or the like. Useful. Anti-epileptic drugs that can be used in conjunction with the present invention, including carbamazepine, gabapentin, lamotrigine, oxcarbazepine, phenytoin, topiramate, and valproate.

Diabetic nephropathy

The NO by-products in the urine of rats treated with streptozotocin were increased, and the increased NO synthesis was associated with high filtration of diabetic glomeruli. The isoforms of neurons, nNOS, are expressed in the loop of Henle and mucula densa of the kidney, and the isoform is inhibited by 7-NI. Isomers reduce renal pelvic filtration without affecting renal arterial blood pressure or renal blood flow (Sigmon et al, Gen. Pharmacol. 34(2): 95-100, 2000). Non-selective NOS inhibitors L-NAME and nNOS selective 7-NI can normalize renal high filtration in diabetic animals (Ito et al., J. Lab Clin. Med. 138(3): 177-185, 2001 ). Therefore, administration of the compound of the present invention may be effective for treating kidney disease of diabetes.

Overuse of drugs

Overuse of drugs (MOH) is associated with the combined use of analgesics, opioids, barbiturates, aspirin, NSAIDS, caffeine, and triptan overuse, and is a common problem limiting the usefulness of such drugs ( Diener and Limmroth. Medication-overuse headache: a worldwide problem. Lancet Neurol. 2004: 3, 475-483). It is more than 15 days per month and is usually defined as a headache (Headache Classification Committee. The International Classification of Headache Disorders (2 ^nd Ed). Cephalalgia 2004: 24 (Supple. 1); 9-160). There is a lot of literature showing that acute treatment for migraine or stressful headaches increases the risk of exacerbation of headaches, develops into daily headaches, or may use excessive acute medications to develop resistance to treatment (Zeeberg et.al.Cephalalgia) 2006: 26, 1192-1198). MOH patients usually do not respond to prophylactic administration under overuse of drugs. At present, the choice of treating MOH is to stop taking the drug, even if withdrawal symptoms such as nausea, vomiting and insomnia often occur. Patients with migraine or tension headache who have MOH, when they do not continue to take the drug for 2 months, the frequency of pain is reduced (45%), many patients remain unchanged after withdrawal (48%) or headache is increased (Zeeberg et.al. Cephalalgia 2006: 26,1192-1198). Therefore, there is still an unmet need for patients with MOH.

It is believed that certain characteristics of MOH, such as increased frequency of headaches, enlarged headache area, and development of skin tenderness, are the result of drug-induced trigeminal pain pathways and central sensitization of the periacqueductal gray zone (Waeber and Moskowitz. Therapeutic implications) Of central and peripheral neurologic mechanisms in mifraine. Neurology : 2003, 61 (Suppl. 4); S9-20). Similar to the behavioral sensitization of neurostimulants, repeated administration of headache drugs (eg, triptans) causes cross-allergy between drugs used to treat headaches. Changes in synaptic plasticity involve changes in intracellular calcium and nitric oxide levels. Patients with chronic headache, migraine and MOH showed an increase in platelet nitrate levels. Therefore, MOH sensitization may be caused by changes in the levels of NO and calcium in the CNS (Sarchielli et. al. Nitric oxide pathway, Ca2+, and serotonin content in platelets from patients suffering from chronic daily headache. Cephalalgia 1999: 19; 810-816). If the central sensitization system is developed by nNOS (Cizkova et.al.Brain.Res.Bull. 2002;58(2):161-171, Choi et.al.J.Neurol.Sci. 1996;138(1 -2): 14-20), etc., it is expected that a neuronal nitric oxide synthase inhibitor such as a compound of the present invention, when used in conjunction with other headache drugs, will be useful for the prevention and treatment of MOH. It is expected that treatment of both CTTH and migraine with nNOS inhibitors will not result in the development of MOH.

Gastrointestinal disorders

nNOS constitutes more than 90% of the total NOS in the small intestine. Although iNOS is structurally present, it is responsible for less than 10% of total NOS activity. And eNOS is basically not detectable in the small intestine (Qu XW et.al. Type I nitric oxide synthase (NOS) is the predominant NOS in rat small intestine. Regulation by platelet-activating factor. Biochim Biophys Acta 1999; 1451:211 -217). The main function of nNOS in the intestine is believed to regulate intestinal movement through neuronal message transmission in the NANC component of the nervous system. NO regulates the muscle tone of the esophagus, pylorus, Oddi sphincter, and anus. NO also regulates the reflection of the fundus and the intestinal peristaltic reflex. NOS inhibitors are known to delay gastric emptying and colonic transport (T. Takahashi J. Gastroenterol. 2003; 38(5): 421-30). Thus nNOS inhibitors can be therapeutic in GI dysregulation and useful for delaying gastric emptying and colonic transport. The pour-on syndrome is a disorder in which the food is evacuated from the stomach too fast, and the small intestine is filled with undigested food that is not yet ready to efficiently absorb nutrients in the small intestine, and is often observed after gastrectomy. Therefore, administration of a compound of the present invention may be useful in the treatment of gastrointestinal disorders such as pour syndrome.

Formula combination and its use

In addition to the above formulations, one or more of the compounds of the invention may be used in combination with other therapeutic agents. For example, one or more compounds of the invention may be combined with other NOS inhibitors. Inhibitors useful for this purpose include, but are not limited to US Patent Application No. 09/127,158 (US Patent Publication No. 2001/0007873), 09/325,480 (US Patent No. 6,235,750), 09/403,177 (unpublished), 09/802,086 (US Patent Publication No. 2002/0032191), 09 / 826, 132 (US Patent No. 6,465, 491), 09/740, 385 (US Patent Publication No. 2001/0049379), 09/381, 887 (US Patent No. 6,362, 195), 10/476, 958 (US Patent Publication No. 2004/0242871), 10/483, 140 (US) Pat. Pub. No, 2004/0176422), 10/484, 960 (US Patent No. 7, 119, 109), 10/678, 369 (US Patent Publication No. 2004/0142924), 10/819, 853 (US Patent No. 7,005, 450), 10/938, 891 (US Patent No. 2005/0032847); International Publication No. WO 97/36871, WO 98/24766, WO 98/34919, WO 99/10339, WO 99/11620 and WO 99/62883.

In another embodiment, one or more compounds of the invention may be combined with an antiarrhythmic agent. Examples of antiarrhythmic agents include, but are not limited to, lidocaine and mixiletine.

A GABA-B synergist, an alpha-2-adrenoreceptor synergist, a cholecystokinin antagonist, a 5HT _1B/1D synergist or a CGRP antagonist can also be combined with one or more compounds of the invention. Examples of non-limiting alpha-2-adrenoreceptor synergists include clonidine, lofexidine, and propanolol. Examples of non-limiting cholecystokinin antagonists include those described in L-365, 260; CI-988; LY262691; S0509 or US Patent No. 5,618,811. Examples of non-limiting 5HT _1B/1D synergists which may be combined with the compounds of the invention include: dihydroegotamine, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan or zolmitriptan. Examples of non-limiting CGRP antagonists that can be combined with the compounds of the invention include: quinine analogs, as described in International Publication No. WO9709046, non-peptide antagonists, International Publication No. WO0132648, WO0132649, WO9811128, WO9809630, WO9856779, WO0018764 Said, or other antagonists such as SB-(+)-273779 or BIBN-4096BS.

Substance P antagonists, also known as NK ₁ receptor antagonists, are also useful in combination with one or more compounds of the invention. Inhibitors useful for this purpose include, but are not limited to, those disclosed in U.S. Patent Nos. 3,862,114, 3,912,711, 4,472,305, 4,481,139, 4,680,283, 4,839,465, 5,102,667, 5,162,339, 5,164,372, 5,166,136, 5,232,929, 5,242,944, 5,300,648, 5,310,743, 5,338,845, 5,340,822 5,378,803,5,410,019, 5,411,971, 5,420,297, 5,422,354, 5,446,052, 5,451,586, 5,525,712, 5,527,811, 5,536,737, 5,541,195, 5,594,022, 5,561,113, 5,576,317, 5,604,247, 5,624,950, and 5,635,510; International Publication No. WO 90/05525, WO 91/09844, WO 91/12266, WO 92/06079, WO 92/12151, WO 92/15585, WO 92/20661, WO 92/20676, WO 92/21677, WO 92/22569, WO 93/00330, WO 93/00331, WO 93/01159, WO 93/01160, WO 93/01165, WO 93/01169, WO 93/01170, WO 93/06099, WO 93/10073, WO 93/14084, WO 93/19064, WO 93/21155, WO 94/04496, WO 94/08997, WO 94/29309, WO 95/11895, WO 95/14017, WO 97/19942, WO 97/24356, WO 97/38692, WO 98/02158, and WO 98/07694 European Patent Publication No. 284942, 32700 9, 333174, 336230, 360390, 394989, 428434, 429366, 443132, 446706, 484719, 499313, 512901, 512902, 514273, 514275, 515240, 520555, 522808, 528495, 532456, and 591040.

Suitable classes of antidepressants that can be used in combination with the compounds of the invention include, but are not limited to, norepinephrine recovery inhibitors, selective serotonin recovery inhibitors (SSRIs), selective noradrenaline/ Norepinephrine recovery inhibitors (NARIs), monoamine oxidase inhibitors (MAOs), reversible inhibitors of monoamine oxidase (RIMAs), dual serotonin/noradrenaline recovery inhibitors (SNRIs), alpha-adenoceptor antagonists , norepinephrine and specific serotonergic antidepressants (NaSSAs) and SARS antidepressants.

Non-limiting examples of norepinephrine recovery inhibitors include: tertiary amine sulfhydryls and secondary amine sulfhydryls, such as: adinazolam, amineptine, amitriptyline, amoxapine, butriptyline, demexiptiline, desmethylamitriptyline, desmethylclomipramine, demexiptiline, desipramine, doxepin, Dothiepin, fluacizine, imipramine, imipramineoxide, iprindole, lofepramine, magrotiline, melitracen, metapramine, Norclolipramine, Nortriptyline, Noxiptilin, opipramol, perlapine, pizotifen, pizotyline, propizepine, protriptyline, quinupramine, tianeptine, trimipramine, trimipramine, amiltriptylinoxide, and pharmaceutically acceptable salts thereof.

Non-limiting examples of selective serotonin recovery inhibitors include, for example, clomipramine, femoxetine, fluoxetine, fluvoxamine, paroxetine, and sertraline, and pharmaceutically acceptable salts thereof.

Non-limiting examples of selective noradrenaline/norepinephrine recovery inhibitors include, for example, atomoxetine, bupropion; reboxetine, tomoxetine, and viloxazine, and pharmaceutically acceptable salts thereof.

Non-limiting examples of selective monoamine oxidase inhibitors include, for example, isocarboxazid, phenelzine, tranylcypromine, and selegiline, and pharmaceutically acceptable salts thereof. Other monoamine oxidase inhibitors useful in combination with the present invention include: clorgyline, cimoxatone, befloxatone, brofaromine, bazinaprine, BW-616U (Burroughs Wellcome), BW-1370U87 (Burroughs Wellcome), CS-722 (RS-722) (Sankyo) , E-2011 (Eisai), harmine, harmaline, moclobemide, PharmaProjects 3975 (Hoechst), RO 41-1049 (Roche), RS-8359 (Sankyo), T-794 (Tanabe Seiyaku), toloxatone, KY 1349 (Kalir and Youdim), LY-51641 (Lilly), LY-121768 (Lilly), M&B 9303 (May & Baker), MDL 72394 (Marion Merrell), MDL 72392 (Marion Merrell), sercloremine, and MO 1671, and pharmaceutically acceptable salts thereof. Suitable monoamine oxidase reversible inhibitors which may be used in the present invention include, for example, moclobemide, and pharmaceutically acceptable salts thereof.

Non-limiting examples of dual serotonin/norepinephrine recovery blockers include, for example, duloxetine, milnacipran, mirtazapine, Nefazodone, and venlafaxine.

Other non-limiting examples of antidepressants useful in the methods of the invention include: adinazolam, alaproclate, amineptine, amitriptyline amitriptyline/chlordiazepoxide combination, atipamezole, azamaneserin, bazinaprine, befuraline, bifemelane, binodaline, bipenamol, brofaromine, caroxazone, cericlamine, cianopramine, Cimoxatone,citalopram,clemeprol,clovoxamine,dazepinil,deanol,demexiptiline,dibenzepin,dimetacrine,dothiepin,droxidopa,enefexine,estazolam,etoperidone,fengabine,fezolamine,fluotracen,idazoxan,indalpine,indeloxazine,levoprotiline,litoxetine;medifoxamine,metalindole,mianserin, Minaprine, montirelin, Nebracetam, Nefopam, Nialamide, Nomifensine, Norfluoxetine, orotirelin, oxaflozane, pinazepam, pirlindole, Ritanserin, Rolipram, sercloremine, setiptiline, sibutramine, Sulbutiamine, sulpiride, teniloxazine, thozalinone, thyroliberin, tiflucarbine, tofenacin, tofisopam, toloxatone, veralipride, viqualine, zimelidine, and zometapine, and pharmaceutically acceptable salts thereof, and St. John's wort herb, or Hypencuin perforatum, or extract thereof Things.

In another embodiment, the opioid can be combined with one or more compounds of the invention. Opium for this purpose includes, but is not limited to, alfentanil, butorphanol, buprenorphine, dextromoramide, dezocine, dextropropoxyphene, treatable Codeine, codeine, diphenoxylate, etorphine, fentanyl, hydrocodone, hydromorphone, phenol Ketobemidone, loperamide, levorphanol, levomethadone, meptazinol, methadone, morphine, morphine-6-glucoside, sodium Nalbuphine, naloxone, oxycodone, oxymorphone, pentazocine, pethidine, piritramide, propoxyphene , remifentanil, sulfentanyl, tilidine and tramadol.

In still other embodiments, anti-inflammatory compounds, such as steroids or non-steroidal anti-inflammatory drugs (NSAIDs), can be combined with one or more Combination of compounds of the invention. Examples of non-limiting steroid agents include: prednisolone and cortisone. Examples of non-limiting NSAIDs include: acemetacin, aspirin, celecoxib, deracoxib, diclofenac, diflunisal, ethenzamide, etofenamate, etoricoxib, fenoprofen, flufenamic acid, flurbiprofen, lonazolac, lornoxicam, ibuprofen, indomethacin, isoxicam, kebuzone, ketoprofen, ketorolac, Naproxen, Nabumetone, Niflumic acid, sulindac, tolmetin, piroxicam, meclofenamic acid, mefenamic acid, meloxicam, metamizol, mofebutazone, oxyphenbutazone, parecoxib, phenidone, phenylbutazone, piroxicam, propacetamol, propyphenazone, Rofecoxib, salicylamide, suprofen, tiaprofenic acid, tenoxicam, valdecoxib , 4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide, N-[2-(cyclohexyloxy)-4-nitrophenyl]methane Indoleamine, 2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methylbutoxy)-5-[4-(methylsulfonyl)phenyl]-3 ( 2H)-tetrahydropyridazinone and 2-(3,5-difluorophenyl)-3-[4-(methylsulfonyl)phenyl]-2-cyclopenten-1-one). The compounds of the invention may also be combined with acetaminophen.

Any combination of the above may be used to treat any suitable disease, disorder or condition. Examples of the use of the compounds of the present invention and other therapeutic agents are described below.

An opioid-NOS inhibitor composition for chronic, neuropathic pain

Nerve damage can lead to abnormal pain states called neuropathic pain. Some clinical symptoms include tactile tenderness (response to the sensation of normal harmless mechanical stimuli), hyperalgesia (enhanced pain intensity response to normal pain stimuli), and spontaneous pain. Spontaneous pain, tenderness, and hyperalgesia caused by neuropathic pain in the rat model of spinal nerve junction (SNL) is similar to the clinical symptoms observed in human patients (Kim and Chung, Pain 50:355 -363, 1992; Seltzer, Neurosciences 7:211-219, 1995).

Neuropathic pain may be particularly insensitive to opioid therapy (Benedetti et al., Pain 74:205-211, 1998) and is still considered to be difficult to treat with opioid analgesia (MacFarlane et al., Pharmacol. Ther. 75: 1-19, 1997; Watson, Clin . J. Pain 16: S49-S55, 2000). Although increasing doses can overcome the reduced opioid effect, they are limited by increased side effects and tolerance. Morphine administration is known to activate the NOS system, which limits the analgesic effects of the drug (Machelska et al, NeuroReport 8: 2743-2747, 1997; Wong et al, Br. J. Anaesth. 8 5 : 587, 2000). ; Xiangqi and Clark, Mol. Brain. Res. 95: 96-102, 2001). However, according to the combined systemic administration of morphine and L-NAME, it is possible to reduce the mechanical and cold tenderness at a dose below the threshold, which is not the effect of any of the drugs alone (Ulugol et al. Neurosci . Res. Com. 30 (3): 143-153, 2002). The analgesic effect of co-administered L-NAME and morphine was shown to be mediated by nNOS, since L-NAME lost its ability to morphine analgesia in mice without nNOS mutations (Clark and Xiangqi, Mol. Brain . Res . 95:96) -102, 2001). Increased analgesic effects have been demonstrated in co-administered L-NAME or 7-NI and mu-, delta- or kappa-selective opioid synergists among tail-flick or paw compression patterns. Proof of proof is obtained (Machelska et al. , J. Pharmacol. Exp. Ther. 282: 977-984, 1997).

Although opioids are an important treatment for the treatment of moderate to severe pain, in addition to limiting the usual side effects of their use, some plausible opioid-induced hyperalgesia may actually make the patient feel more sensitive to pain. It also aggravates the pain (Angst and Clark, Anesthesiology, 2006, 104(3), 570-587; Chu et al, J. Pain 2006, 7(1) 43-48). The development of tolerance and hyperalgesia caused by opioids are consistent with an increase in the level of NO production in the brain. The reduction in opioid analgesic effect is due to a NO-induced up-regulation of hyperalgesia response (Heinzen and Pollack, Brain Res. 2004, 1023, 175-184).

Thus, combining nNOS inhibitors with opioids (such as combinations described above) enhances the analgesic pain of opioids in neuropathic pain and inhibits the production of opioid tolerance and opioid-induced hyperalgesia.

Antidepressant-NOS inhibitor composition against chronic pain, neuropathic pain, chronic headache or migraine

Many antidepressants are used to treat neuropathic pain (McQuay et al, Pain 68: 217-227, 1996) and migraine (Tomkins et al, Am. J. Med. 111: 54-63, 2001) and Serotonin production or adrenaline system action. NO acts as a neuromodulator for these systems (Garthwaite and Boulton, Annu. Rev. Physiol . 57: 683, 1995). 7-NI has been shown to release noradrenaline (NA) by the nicotinic acid acetylcholine receptor synergist DMPP via the NA transporter (Kiss et al, Neuroscience Lett, 215: 115-118, 1996). ). Topical administration of antidepressants such as paroxetine, tianeptine and imipramine reduces the level of hippocampal NO (Wegener et al, Brain Res. 959: 128-134, 2003). NO may be important in the mechanism by which antidepressants can effectively treat pain and depression, and combined with nNOS inhibitors and antidepressants, such as the combinations described above, will provide better treatment.

Serotonin 5HT _1B/1D/1F Synergistic or CGRP antagonists and NOS inhibitors against migraine

Administration of nitroglycerin (GTN)-NO provider causes immediate headache in normal individuals and delays migraine attacks during a 4-6 hour delay (Iversen et al., Pain 38: 17-24, 1989) ). For patients with migraine, CGRP levels (peptides associated with the calcitonin gene), a useful vasodilator, are associated with the onset and extinction of the carotid artery and migraine (Durham, Curr Opin Investig Drugs) 5(7): 731-5, 2004). Sumatriptan, an anti-migraine drug with affinity for 5HT _1B , 5HT _1D and 5HT _1F receptors, relieves GTN-induced immediate headaches and similar contractions of the brain and outer brain (extresrebral) (Iversen and Olesen, Cephalagia 13 (Suppl 13): 186, 1993). The anti-migraine drug rizatriptan also reduces cytoplasmic CGRP levels after migraine pain is reduced (Stepien et al, Neurol. Neurochir. Pol. 37(5): 1013-23, 2003). Therefore, both NO and CGRP are involved in migraine. In brain cortical sections, serotonin 5HT _1B/1D synergists have been shown to block NMDA receptor-primed NO signaling (Strosznajder et al, Cephalalgia 19(10): 859, 1999). These results indicate that combining the compounds of the invention with a selective or non-selective 5HT _1B/1D/1F synergist or CGRP antagonist, such as the above combinations, may be useful for the treatment of migraine.

Pharmaceutical composition

The compounds of the present invention are preferably formulated into pharmaceutical compositions for proper administration into a human in a biologically compatible form. In summary, in other aspects, the invention provides a pharmaceutical composition comprising a mixture of a compound of the invention and a suitable diluent, carrier or excipient.

The compounds of the invention are useful in free base forms, salt forms, solvates and prodrugs. All forms are within the scope of the invention. In accordance with the methods of the present invention, the compound or salt, solvate or prodrug can be administered to a patient in a variety of forms depending on the route of administration selected by those skilled in the art. The compounds of the invention may be, for example, orally, parenterally, buccally, sublingually, nasally, rectally, via patch, via a fistula or percutaneously The skin is administered and the pharmaceutical composition is formulated accordingly. In summary, non-oral administration includes: intravenous, intraperitoneal, subcutaneous, intramuscular, epithelial, nasal, intrapulmonary, intrathecal, transrectal and topical administration. Non-oral administration can be continuously perfused for a period of selection.

The compounds of the present invention can be administered orally, for example, together with an inactive diluent or an edible absorbable carrier, or in a hard or soft gelatin capsule shell, or compressed into tablets, or directly with food. edible. Orally therapeutically administered compounds of the invention may be administered together with excipients in the form of digestible tablets, buccal tablets, guilloche, capsules, alcohols (elixir), suspensions, syrups, tablets Wait.

The compounds of the invention may be administered parenterally. A solution of the compound of the present invention can be prepared by suitably mixing with a surfactant, hydroxypropylcellulose, in water. Dispersing agents can also be prepared in oils with or without glycerol, liquid polyethylene glycol, DMSO, and mixtures thereof. Such preparations may contain a preservative to inhibit microbial growth under normal conditions of storage and use. The known procedures and selection and preparation of suitable formulations are described, for example, in Remington's Pharmaceutical Sciences (2003-20th edition) and the United States Pharmacopoeia: The National Formulary (USP 24 NF19) 1999.

Suitable pharmaceutical forms for injection molding, including sterile aqueous solutions, or dispersions and sterile powder dispersions for the preparation of sterile injectable solutions or dispersions. In all cases, it must be sterile and fluid to enable easy administration via a syringe.

The nasally administered composition can be conveniently formulated into an aerosol, a drop, and a gel. Gum and powder. Aerosol formulations typically comprise a solution or a suspension of the active substance in a physiologically acceptable aqueous or nonaqueous solvent, and usually in a sealed container in the form of a single or multiple doses in a sterile form, the container may be in the form of a cartridge Or a spray device that can be refilled. Alternatively, the sealed container can be a single dispensing device, such as a single dose nasal inhaler or an aerosol dispenser with a metering valve that can be disposed of after use. Wherein, the dosage form comprising the aerosol dispenser will comprise a propellant which may be a compressed gas such as an organic propellant such as a chlorofluorocarbon. The aerosol dosage form can be a cartridge sprayer.

Suitable buccal or sublingual administration compositions, including: lozenges, lozenges, and pastilles, wherein the active ingredient is formulated with a carrier comprising: sugar, gum arabic, tragacanth or Gelatin and glycerin. The rectal administration of the composition can be conveniently made into a suppository containing a conventional suppository base such as cocoa butter.

The compounds of the present invention can be administered alone or together with a pharmaceutically acceptable carrier, the ratio of which is determined by chemical solubility, chemical nature, and the chosen route of administration and standard pharmaceuticals. It depends on the specification.

The dosage of a compound of the invention and/or a composition comprising a compound of the invention depends on a number of factors, for example, the pharmacokinetic properties of the compound; the mode of administration; the age, health and weight of the recipient; the nature of the symptoms And scope; the frequency of treatment and, if any, the form of simultaneous treatment; and the clearance rate of the compound in the animal being treated. Those skilled in the art can determine the appropriate dosage based on the above factors. The compound of the present invention can be initially administered in an appropriate dose, which can Adjust according to clinical response. In general, satisfactory results are obtained when the compound of the present invention is administered to humans at a daily dose of 0.05 mg to 3000 mg (measured in solid form). A preferred dose is between 0.05 and 500 mg/kg, more preferably between 0.5 and 50 mg/kg.

The compounds of the invention may be used alone or in combination with other agents having NOS activity, or in combination with other forms of treatment (which may or may not inhibit NOS) to treat, inhibit and/or reduce stroke, neurological or migraine pain or other The benefits of inhibiting the risk of NOS imbalance. Combinations of one or more therapeutic compound doses can be reduced compared to standard doses administered separately. In this case, the dose of the compound when combined should provide a therapeutic effect.

In addition to the above therapeutic uses, the compounds of the invention are also useful in diagnostic assays, screening assays, and research tools.

In diagnostic assays, the compounds of the invention may be useful in identifying or detecting NOS activity. For this use, the compound can be radiolabeled (as described elsewhere) and contacted with a cell population of the organism. The presence of a radioactive label on the cell may indicate NOS activity.

In screening assays, the compounds of the invention can be used to identify other compounds that inhibit NOS, such as first generation drugs. As a research tool, the compounds of the present invention can be used in an enzyme assay and to test the position of NOS activity. This information may be useful, for example, in diagnosing or monitoring a disease state or process. The compounds of the invention can be radiolabeled.

NOS in vivo inhibition test

Compounds of the invention have been found to exhibit selective inhibition of neuronal isoforms of NOS (nNOS). Depending on the person skilled in the art, for example Using the methods described in Examples 19a and 19b below, the test compounds preferably inhibited nNOS more than iNOS and/or eNOS.

The following non-limiting examples illustrate the invention:

Example Example 1.

6-nitro-1-(2-(piperidin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one

6-Nitro-3,4-dihydroquinolin-2(1H)-one (400 mg, 2.08 mmol), 1-(2-chloroethyl)piperidine hydrogen chloride (421 mg, 2.29 mmol) and potassium carbonate ( A suspension of 862 mg, 6.24 mmol) in 10 mL of DMF was stirred at room temperature overnight. After the mixture was poured into 20mL H ₂ O and then extracted with 2 × 50mL CH ₂ Cl _2. The organic layer was separated, washed with brine and concentrated to give a yellow-brown solid, which was subjected to flash chromatography on silica, using 5% MeOH / CH ₂ Cl ₂ to give a yellow viscous oil (560mg, 88.7% ). ¹ H-NMR (CDCl ₃ ) δ: 8.14 (dd, J = 2.7, 9 Hz, 1H), 8.06-8.05 (m, 1H), 7.24 (d, J = 9.0 Hz, 1H), 4.11 (t, J = 7.2 Hz, 2H), 3.02-2.95 (m, 2H), 2.73-2.67 (m, 2H), 2.57-2.48 (m, 6H), 1.59-1.44 (m, 6H).

MS (ESI): 304.2 (M+1, 100%).

6-Amino-1-(2-(piperidin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one

A solution of 6-nitro-1-(2-(piperidin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one (500 mg, 1.65 mmol) in 10 mL of methanol A round bottom flask was added to Raney Nickel (slurry in water, 50 mg). The suspension was heated to reflux for 10 minutes and then filtered through a pad of Celite. The diatomaceous earth pad was washed with 10 mL of methanol. The filtrate was concentrated to give a dark brown residue was subjected to flash silica gel chromatography using 5% 2M NH ₃ in MeOH / CH ₂ Cl ₂ to give an off-white solid (350mg, 77.7%). ¹ H-NMR (DMSO-d ₆ ) δ: 6.81 (d, J = 8.2 Hz, 1H), 6.46-6.41 (m, 2H), 4.84 (br s, 2H), 3.87 (t, J = 7.1 Hz, 2H), 2.66 (t, J = 6.5 Hz, 2H), 2.40-2.32 (m, 8H), 1.46-1.35 (m, 6H); MS (ESI): 274.2 (M+1, 100%).

N-(2-Sideoxy-1-(2-(piperidin-1-yl)ethyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboxyindole Amine

A solution of 6-amino-1-(2-(piperidin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one (225 mg, 0.82 mmol) in 10 mL of EtOH The methylthiophene-2-carboquinone thiocarboxylate hydrogen iodide (470 mg, 1.65 mmol) was treated and stirred at room temperature overnight. TLC analysis indicated that the starting amine was still present. An additional 235 mg of methylthiophene-2-carboquinone thiocarboxylate hydrogen iodide was added and stirring was continued for 1 day. Argon was bubbled into the mixture for 20 minutes and then concentrated to give a brown oil. The residue is partitioned between 10% MeOH in of CH ₂ Cl ₂ (50mL) and saturated sodium bicarbonate (20mL). The aqueous layer was an additional 50mL CH ₂ Cl ₂ extracted with. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to give a brown residue which was subjected to flash chromatography on silica, using 5% MeOH / CH ₂ Cl ₂ to 10% 2M NH ₃ in MeOH / CH ₂ Cl ₂ gave a yellow solid which contained a mixture of starting amine and desired product. This mixture was applied as a preparative TLC using 10% MeOH: 10% Et3N: 80% EtOAc as eluent. A small amount of the product was obtained in pure form (by HPLC). This compound was dissolved by 10mL of 10% MeOH / CH ₂ Cl ₂ was converted to the dihydrochloride salt, was cooled to 0 deg.] C, and 1M HCl in Et ₂ O solution treatment at 0.5mL. The solution was stirred for 20 minutes and concentrated to give a yellow brown oil. After drying overnight under high vacuum, a yellow solid was obtained. Yield: 12 mg of compound 1. HPLC analysis showed the product to be >99% pure. ¹ H-NMR (MeOH-d ₄ ) δ: 8.08-8.05 (m, 2H), 7.40-7.38 (m, 4H), 4.42 (t, J = 6.7 Hz, 2H), 3.77-3.73 (m, 2H) , 3.41 (t, J = 6.7 Hz, 2H), 3.32-3.02 (m, 4H), 2.76-2.72 (m, 2H), 2.00-1.53 (m, 6H); MS (ESI): 383.2 (M+1) ), 30%, 192.1 (M+2), 100%. ESI-HRMS calculated for C ₂₁ H ₂₇ N ₄ OS (MH ⁺ ): 383.1900, observed: 383.1908.

Example 2.

1-(2-(Diethylamino)ethyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one

6-Nitro-3,4-dihydroquinolin-2(1H)-one (400 mg, 2.08 mmol), 2-chloro-N,N-diethylethylamine hydrogen chloride (394 mg, 2.29 mmol) and carbonic acid A suspension of potassium (862 mg, 6.24 mmol) in 10 mL of DMF was stirred at room temperature overnight. After the mixture was poured into 20mL H ₂ O and then extracted with 2 × 50mL CH ₂ Cl _2. The organic layer was separated, washed with brine and concentrated to give a yellow-brown solid which was subjected to flash chromatography on silica, using 5% MeOH / CH ₂ Cl ₂ to give a yellow viscous oil (585mg, 96.5%) . ¹ H-NMR (CDCl ₃ ) δ: 8.16 (dd, J = 2.5, 9 Hz, 1H), 8.06 (d, J = 2.5 Hz, 1H), 7.23 (d, J = 9.0 Hz, 1H), 4.07 (t , J = 7.0 Hz, 2H), 3.00 (t, J = 7.0 Hz, 2H), 2.73 - 2.55 (m, 8H), 1.01 (t, J = 7.0 Hz, 6H).

MS (ESI): 292.2 (M+1, 100%).

6-Amino-1-(2-(diethylamino)ethyl)-3,4-dihydroquinolin-2(1H)-one

A solution of 1-(2-(diethylamino)ethyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (500 mg, 1.72 mmol) in 10 mL of methanol The bottom flask was added to Raney Nickel (slurry in water, 50 mg). This suspension was treated with hydrazine hydrate (534 [mu]L, 17.2 mmol) and heated to reflux for 10 min then filtered over a pad. The diatomaceous earth pad was rinsed with 10 mL of methanol. The filtrate was concentrated to give a dark brown residue which was subjected to flash silica gel chromatography using 5% 2M NH ₃ in MeOH / CH ₂ Cl ₂ to give a colorless oil (365mg, 81.2%). ¹ H-NMR (CDCl ₃ ) δ: 6.88 (d, J = 8.4 Hz, 1H), 6.58 (d, J = 2.7 Hz, 1H), 6.51 (dd, J = 2.7, 9 Hz, 1H), 3.98 (t , J = 7.8 Hz, 2H), 3.54 (br s, 2H), 2.78 (t, J = 7.8 Hz, 2H), 2.66-2.55 (m, 8H), 1.04 (t, J = 7.2 Hz, 6H). MS (ESI): 262.2 (M+1, 100%).

N-(1-(2-(diethylamino)ethyl)-2-yloxy-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboximine Guanamine

A solution of 6-amino-1-(2-(diethylamino)ethyl)-3,4-dihydroquinolin-2(1H)-one (275 mg, 1.05 mmol) in 10 mL of EtOH The thiophene-2-carbonium imine thiocarboxylate hydrogen iodide (600 mg, 2.10 mmol) was treated and stirred at room temperature for 4 days. Argon pump the mixture into the 20 minutes, the mixture was partitioned between CH ₂ Cl ₂ Room (50mL) and saturated sodium bicarbonate (10mL). The aqueous layer was an additional 20mL CH ₂ Cl ₂ extracted with. The combined organic layers were dried over sodium sulfate and concentrated to give a yellow residue which was subjected to flash chromatography on silica, using _{5% MeOH / CH 2 Cl 2} , followed by 5% 2M NH ₃ in MeOH / CH ₂ Cl ₂ to A yellow solid (170 mg, 43.7%) was obtained. HPLC analysis showed the product to be >99% pure. ¹ H-NMR (DMSO-d ₆ ) δ: 7.73 (d, J = 3.6 Hz, 1H), 7.60 (d, J = 4.8 Hz, 1H), 7.11-7.04 (m, 2H), 6.76-6.74 (m, 2H), 6.42 (brs, 2H), 3.92 (t, J = 7 Hz, 2H), 2.80 (t, J = 7 Hz, 2H), 2.56-2.47 (m, 8H), 0.94 (t, J = 7 Hz, 6H).

MS (ESI): 371.2 (M+1). ESI-HRMS calcd for C ₂₀ H ₂₇ N ₄ SO (MH ⁺ ): 371.1900, observed: 371.1906.

Example 3.

6-nitro-3,4-dihydroquinolin-2(1H)-one

For a 250 mL round bottom flask containing 3,4-dihydro-2-(1H)-quinoline (3.00 g, 20.38 mmol) and a magnetic stir bar, concentrated sulfuric acid (60 mL) was added. The argon aerated reaction was placed in an ice-methanol bath (~-10 ° C) and stirred to dissolve the solid. Distilled water (15 mL) was added. A fuming nitric acid in water (2.86 mL, 20.43 mmol) 45% solution was added dropwise to this colorless reaction. The orange-red solution was stirred at -10 ° C for 25 minutes. The reaction was quenched by pouring it into ice-water melt (300 mL). The ice was melted and collected by vacuum filtration to collect a yellow solid. The solid was washed with water (3.50 mL). After drying by suction, the product was washed again with ether (3 x 30 mL). TLC (1:1 EtOAc:hexanes) showed some starting material. The product was washed on a filter with dichloromethane (2×30 mL). TLC showed the solid to be the pure desired product, and the filtrate contained both the starting material and the product. Yield: 3.20 g of yellow solid (82%). ¹ H NMR (DMSO- d ₆ ) δ: 10.68 (br s, 1H), 8.11 (s, 1H), 8.07 (d, J = 8.7 Hz, 1H), 7.00 (d, J = 8.7 Hz, 1H), 3.01 (t, J = 7.2 Hz, 2H), 2.53 (t, J = 7.8 Hz, 2H).

1-(2-(Dimethylamino)ethyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one

6-Nitro-3,4-dihydroquinolin-2(1H)-one (500 mg, 2.60 mmol), (N,N-dimethylamino)ethyl chlorohydrochloride (412 mg, 2.86 mmol) A suspension of potassium carbonate (1.07 g, 7.74 mmol) in 8 mL of DMF was stirred at room temperature for 48 h. (N,N-Dimethylamino)ethyl chlorohydrochloride (187 mg, 1.30 mmol) and potassium carbonate (359 mg, 2.60 mmol) were added. The reaction was stirred for an additional 16 hours. After that, the reaction was transferred to a sep. funnel and diluted with cold water and ethyl acetate. The aqueous layer was extracted twice more with EtOAc (EtOAc)EtOAc. The residue was subjected to flash chromatography on silica gel using 5% 2M NH ₃ in MeOH / CH ₂ Cl ₂ to give a yellow solid. Yield: 370 mg (54%). ¹ H NMR (CDCl ₃ ) δ: 8.15 (dd, J = 2.7, 9.0 Hz, 1H), 8.06 (d, J = 2.7 Hz, 1H), 7.17 (d, J = 9 Hz, 1H), 4.09 (t, J = 7.2 Hz, 2H), 3.00 (t, J = 6.6 Hz, 2H), 2.71 (t, J = 7.5 Hz, 2H), 2.52 (t, J = 7.5 Hz, 2H), 2.32 (s, 6H) . MS (ESI): 264.1 (M+1).

6-Amino-1-(2-(dimethylamino)ethyl)-3,4-dihydroquinolin-2(1H)-one

1-(2-(Dimethylamino)ethyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (320 mg, 1.215 mmol) in anhydrous methanol (10 mL) The suspension was treated with Ra-Ni (~0.05 g) and then taken with hydrazine hydrate (0.38 mL, 12.2 mmol) at room temperature and the mixture was refluxed for 20 min. The colorless reaction was cooled to rt, filtered over EtOAc EtOAc (EtOAc) The combined methanol layer was evaporated and the crude product was purified by column chromatography to (2M NH ₃ in _{MeOH: CH 2 Cl 2, 5} : 95). Yield: 280 mg of colorless oil (98%). ¹ H NMR (CDCl ₃ ) δ: 6.86 (d, J = 8.4 Hz, 1H), 6.57 (dd, J = 2.7, 8.4 Hz, 1H), 6.51 (d, J = 2.1 Hz, 1H), 4.01 (t , J = 7.5 Hz, 2H), 2.78 (t, J = 7.2 Hz, 2H), 2.58 (t, J = 7.2 Hz, 2H), 2.51 (t, J = 7.2 Hz, 2H), 2.31 (s, 6H) ). MS (ESI): 234.2 (M+1).

N-(1-(2-(Dimethylamino)ethyl)-2-yloxy-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboximine Guanamine:

6-Amino-1-(2-(dimethylamino)ethyl)-3,4-dihydroquinolin-2(1H)-one (0.280 g, 1.20 mmol) in absolute ethanol (5 mL) The solution was treated with methylthiophene-2-carbomine imine thiocarboxylate hydrogen iodide (0.684 g, 2.40 mmol) at room temperature and the mixture was stirred overnight (18 h). The reaction was diluted with ether (45 mL) and the precipitate was collected in vacuo. The precipitate was washed from the filter with methanol and the solvent was evaporated. The residue was diluted with 1N aqueous sodium hydroxide (5 mL). The combined ethyl acetate layer was washed with brine and dried (Na ₂ SO _4). The solvent was evaporated and the crude material was purified eluting elut elut elut The product was dried under high vacuum. Yield: 230 mg yellow oil 3 (56%). ¹ H NMR (CDCl ₃ ) δ: 7.44 (dd, J = 1, 5.4 Hz, 1H), 7.41 (d, J = 3.3 Hz, 1H), 7.09 (t, J = 4.2 Hz, 1H), 7.03 (d) , J = 8.4 Hz, 1H), 6.88 (dd, J = 2.1, 8.4 Hz, 1H), 6.83 (d, J = 2.1 Hz, 1H), 4.87 (br s, 2H), 4.06 (t, J = 7.5) Hz, 2H), 2.86 (t, J = 7.2 Hz, 2H), 2.63 (t, J = 7.2 Hz, 2H), 2.55 (t, J = 7.2 Hz, 2H), 2.33 (s, 6H). MS (ESI): 357.2 (M+1). ESI-HRMS calcd for C ₁₈ H ₂₃ N ₄ SO (MH ⁺ ): 343.1587, observed: 343.1598.

Example 4:

1-(3-chloropropyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one

6-Nitro-3,4-dihydroquinolin-2(1H)-one (1.50 g, 7.81 mmol) was dissolved in dry DMF (30 mL) EtOAc. The reaction was stirred in an ice-water bath and a portion of 60% sodium hydride over EtOAc (EtOAc &lt The reaction turned dark red-orange. This solution was transferred using a trocar to a solution of 1-chloro-3-iodopropane (2.52 mL, 23.47 mmol) in DMF (20 mL). The reaction was stirred at room temperature for 5 hours. The reaction was quenched with EtOAc (EtOAc) (EtOAc)EtOAc. The aqueous layer was extracted twice more with ethyl acetate (2×20 mL). The combined organic layers were washed with brine, dried over sodium sulfate Purification by flash column chromatography gave a yellow solid (ethyl acetate:hexane: 30: 70-100:0). ¹ H NMR (DMSO- d ₆ ) δ: 8.16 (s, 1H), 8.13 (d, J = 2.7 Hz, 1H), 7.36 (d, J = 8.7 Hz, 1H), 4.09 - 4.04 (m, 2H) , 3.71 (t, J = 6.3 Hz, 2H), 3.01 (t, J = 7.5 Hz, 2H), 2.66 - 2.61 (m, 2H), 2.04-1.99 (m, 2H). MS (ESI): 291.0 and 293.0 (M+1).

1-(3-(Dimethylamino)propyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one

1-(3-Chloropropyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (300 mg, 1.12 mmol), demethylamine hydrogen chloride (911 mg, 11.16 mmol), Potassium iodide (1.85 g, 11.16 mmol) and potassium carbonate (1.54 g, 11.16 mmol) were weighed into an argon-vented vial equipped with a magnetic stir bar. Anhydrous acetonitrile was added and the yellow suspension was stirred at room temperature for 18 h. The reaction was placed in a heated block at a temperature of 60 ° C for 2 hours. After cooling to room temperature, the reaction was filtered through EtOAc (EtOAc)EtOAc. No further purification was carried out. Yield: 520 mg of crude material. ¹ H NMR (DMSO- d ₆ ) δ: 8.11 (d, J = 2.4 Hz, 1H), 8.06 (dd, J = 2.7 Hz, 9.3 Hz, 1H), 7.41 (d, J = 9 Hz, 1H), 3.94 (t, J = 7.2 Hz, 2H), 2.99 (t, J = 6.9 Hz, 2H), 2.73 (s, 6H), 2.59 (t, J = 8.1 Hz, 2H), 2.45 (t, J = 1.5 Hz) , 2H), 1.86 (t, J = 7.5 Hz, 2H). MS (ESI): 278.1 (M+1).

6-Amino-1-(2-(dimethylamino)ethyl)-3,4-dihydroquinolin-2(1H)-one

1-(3-(Dimethylamino)propyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (0.510 g, 1.84 mmol) in anhydrous methanol (10 mL) Treatment with Ra-Ni (~0.05 g) followed by hydrazine hydrate (0.58 mL, 18.4 mmol) at room temperature and the mixture was refluxed for 20 min. The reaction was cooled to rt, filtered over EtOAc EtOAc (EtOAc) The combined methanol layer was evaporated and the crude product was purified by column chromatography to (2M NH ₃ in _{MeOH: CH 2 Cl 2, 5} : 95). Yield: 90 mg of yellow solid (20%). ¹ H NMR (CDCl ₃ ) δ: 6.86 (d, J = 8.4 Hz, 1H), 6.56 (dd, J = 2.7, 8.4 Hz, 1H), 6.52 (d, J = 2.1 Hz, 1H), 3.92 (t , J = 7.2 Hz, 2H), 2.79 (t, J = 7.2 Hz, 2H), 2.59 (t, J = 7.2 Hz, 2H), 2.35 (t, J = 7.2 Hz, 2H), 2.23 (s, 6H) ), 1.85-1.75 (m, 2H). MS (ESI): 248.2 (M+1)

N-(1-(2-(Dimethylamino)ethyl)-2-yloxy-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboximine Guanamine

6-Amino-1-(2-(dimethylamino)ethyl)-3,4-dihydroquinolin-2(1H)-one (0.045 g, 0.182 mmol) in dry ethanol (5 mL) The solution was treated with methylthiophene-2-carbomine thiocarboxylate hydrogen iodide (0.103 g, 0.361 mmol) at room temperature and the mixture was stirred overnight (18h). The reaction was diluted with ether (45 mL) and the precipitate was collected in vacuo. This precipitate was washed from the filter with methanol, and the solvent was evaporated. The residue was diluted with 1N aqueous sodium hydroxide (5 mL). The combined ethyl acetate layer was washed with brine and dried (Na ₂ SO _4). The solvent was evaporated and the crude material was purified eluting elut elut elut The product was dried under high vacuum. Yield: 40 mg of yellow oil 4 (58%) ¹ H NMR (CDCl ₃ ) δ 7.44 (dd, J = 1, 5.4 Hz, 1H), 7.41 (d, J = 3.3 Hz, 1H), 7.09 (t, J = 4.2 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.88 (dd, J = 2.1, 8.4 Hz, 1H), 6.83 (d, J = 2.1 Hz, 1H), 4.87 (br s, 2H) ), 3.98 (t, J = 7.2 Hz, 2H), 2.87 (t, J = 7.2 Hz, 2H), 2.63 (t, J = 7.2 Hz, 2H), 2.37 (t, J = 7.2 Hz, 2H), 2.25 (s, 6H), 1.89-1.79 (m, 2H). MS (ESI): 357.2 (M+1). ESI-HRMS calcd for C ₁₉ H ₂₅ N ₄ SO (MH ⁺ ): 357.1743, observed: 357.1752.

Example 5:

1-(3-morpholinylpropyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one

1-(3-Chloropropyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (100 mg, 0.359 mmol), morpholine (313 uL, 3.59 mmol), potassium iodide (596 mg) , 3.59 mmol) and potassium carbonate (496 mg, 3.59 mmol) were weighed into a vial ventilated with argon gas, and the vial was equipped with a magnetic stir bar. Anhydrous acetonitrile (4 mL) was added, and the yellow suspension was stirred at <RTIgt; When the starting material remained, the reaction was stirred at this temperature for an additional 3 days. After cooling to room temperature, the reaction was diluted with water (10 mL) and dichloromethane (15 mL) and transferred to a sep. The organic layer was collected, and the aqueous layer was extracted twice with dichloromethane (2×10 mL). The combined organic phases were washed with brine (15 mL) and dried over sodium sulfate. This solution was poured out and concentrated to give a yellow oil. The product was purified using flash chromatography (2M NH ₃ in _{MeOH: CH 2 Cl 2, 2.5-5} : 95-97.5) to give a yellow oil. Yield: 88 mg of yellow oil (77%). ¹ H-NMR (CDCl ₃ ) δ: 8.13 (dd, J = 2.7, 9 Hz, 1H), 8.07 (d, J = 2.4 Hz, 1H), 7.21. (d, J = 9.0 Hz, 1H), 4.04 (t) , J = 7.5 Hz, 2H), 3.72 (t, J = 4.5 Hz, 4H), 3.01 (t, J = 7.2 Hz, 2H), 2.73 - 2.68 (m, 2H), 2.46-2.39 (m, 6H) , 1.88-1.79 (m, 2H). MS (EI): 319 (M+)

6-Amino-1-(3-morpholinylpropyl)-3,4-dihydroquinolin-2(1H)-one

1-(3-Morpholinylpropyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (78 mg, 0.244 mmol) in anhydrous methanol (5 mL) ~0.05 g) was treated with hydrazine hydrate (76 uL, 2.44 mmol) at room temperature and the mixture was refluxed for 30 min. The reaction was cooled to room temperature, filtered through a pad of celite and washed with methanol (2×10 mL). The combined methanol layer was evaporated and the crude product was purified by column chromatography to (2M NH ₃ in _{MeOH: CH 2 Cl 2, 2.5} : 97.5). Yield: 64 mg of yellow oil (90%). ¹ H NMR (CDCl 3 ) δ: 6.86 (d, J = 8.4 Hz, 1H), 6.56 (dd, J = 2.7, 8.4 Hz, 1H), 6.52 (d, J = 2.1 Hz, 1H), 3.93 (t, J=7.2 Hz, 2H), 3.71 (t, J=4.5 Hz, 4H), 2.81-2.76 (m, 2H), 2.61-2.56 (m, 2H), 2.44-2.36 (m, 6H) 1.83-1.65 ( m, 2H). MS (ESI): 290.2 (M+1).

N-(1-(3-morpholinopropyl)-2-oxooxy-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboxyindoleimine amide

A solution of 6-amino-1-(3-morpholinopropyl)-3,4-dihydroquinolin-2(1H)-one (0.055 g, 0.190 mmol) in dry ethanol (5 mL) Methylthiophene-2-carbomine imine thiocarboxylate hydrogen iodide (0.108 g, 0.379 mmol) was treated at room temperature and the resulting mixture was stirred for 64 hours. The reaction was transferred to a sep. funnel and diluted with ethyl acetate (30 mL) and sat. The aqueous phase was further partitioned twice with ethyl acetate (2×20 mL). The combined organic phases were washed with brine and dried (Na ₂ SO _4). The solvent was evaporated and the crude material was purified eluting EtOAc EtOAc EtOAc The product was dried under high vacuum to give 5 as a yellow oil. Yield: 36 mg of yellow oil (48%). ¹ H NMR (CDCl ₃ ) δ: 7.44 (d, J = 5.4 Hz, 1H), 7.41 (d, J = 3.3 Hz, 1H), 7.09 (t, J = 4.2 Hz, 1H), 7.06 (d, J) = 8.4 Hz, 1H), 6.88 (d, J = 2.1 Hz, 1H), 6.84 (d, J = 4.2 Hz, 1H), 4.86 (br s, 2H), 4.02-3.97 (m, 2H), 3.73 3.70 (m, 4H), 2.89-2.84 (m, 2H), 2.66-2.61 (m, 2H), 2.46-2.39 (m, 6H), 1.90-1.80 (m, 2H). MS (ESI): 399.2 (m+1). ESI-HRMS calcd for C ₂₁ H ₂₇ N ₄ SO ₂ (MH ⁺ ): 399.1849, observed: 399.1836.

Example 6

6-nitro-1-(2-(pyrrolidin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one

6-Nitro-3,4-dihydroquinolin-2(1H)-one (230 mg, 1.06 mmol), 1-(2-chloroethyl)pyrrolidinium chloride (234 mg, 1.37 mmol) and potassium carbonate ( A suspension of 440 mg, 3.18 mmol) in 5 mL of DMF was stirred at room temperature for 4 days. After the mixture was poured into 20mL H ₂ O and then extracted with 2 × 30mL CH ₂ Cl _2. The organic layers were combined, washed with brine (20 mL) and concentrated. Product was subjected to flash chromatography on biotage, using 5% 2M NH3 in MeOH / CH ₂ Cl ₂ to give a yellow solid. Yield: 218 mg of yellow solid (71%). ¹ H NMR (CDCl ₃ ) δ: 8.14 (dd, J = 2.7, 9 Hz, 1H), 8.06 (d, J = 2.4 Hz, 1H), 7.20 (d, J = 9.0 Hz, 1H), 4.13 (t, J = 7.5 Hz, 2H), 3.00 (t, J = 6.9 Hz, 2H), 2.73 - 2.68 (m, 4H), 2.63 - 2.60 (m, 4H), 1.82-1.78 (m, 4H). MS (ESI): 290.2 (M+1, 100%).

6-Amino-1-(2-(pyrrolidin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one

a solution of 6-nitro-1-(2-(pyrrolidin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one (205 mg, 0.709 mmol) in 5 mL of MeOH. Add to Raney Nickel (slurry in water, 50 mg) in a reaction vial. This suspension was treated with hydrazine hydrate (220 [mu]L, 7.09 mmol) and heated to reflux for 2 h then filtered over a pad. The diatomaceous earth pad was rinsed with 10 mL of methanol. The filtrate was concentrated and the resulting product was subjected to flash chromatography on silica gel using 2.5% 2M NH ₃ in MeOH / CH ₂ Cl ₂ to give a yellow oil. Yield: 180 mg (98%). ¹ H NMR (CDCl ₃ ) δ: 6.89 (d, J = 8.4 Hz, 1H), 6.56 (dd, J = 2.7, 8.4 Hz, 1H), 6.52 (d, J = 2.1 Hz, 1H), 4.04 (t , J = 7.5 Hz, 2H), 2.81-2.76 (m, 2H), 2.71-2.66 (m, 2H), 2.63 - 2.56 (m, 6H), 1.81-1.77 (m, 4H). MS (ESI): 260.2 (M+1, 100%).

N-(2-Sideoxy-1-(2-(pyrrolidin-1-yl)ethyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboxyindole Amine

a solution of 6-amino-1-(2-(pyrrolidin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one (165 mg, 0.636 mmol) in 5 mL of ethanol Methyl thiophene-2-carboquinone thiocarboxylate hydrogen iodide (363 mg, 1.27 mmol) was treated and stirred at room temperature for 18 h. This mixture is layered to between (50mL) and saturated sodium bicarbonate (10mL) CH ₂ Cl _2. The aqueous layer was an additional 20mL CH ₂ Cl ₂ extracted with. The combined organic layers were dried over sodium sulfate and concentrated to give a yellow residue subjected to flash chromatography on a Biotage system using a 5-10% 2M NH ₃ in MeOH / CH ₂ Cl ₂ to give a yellow solid. Yield: 157 mg of yellow oil (68%). ¹ H NMR (CDCl ₃ ) δ: 7.44 (d, J = 5.4 Hz, 1H), 7.41 (d, J = 3.3 Hz, 1H), 7.09 (t, J = 4.2 Hz, 1H), 7.06 (d, J) = 8.4 Hz, 1H), 6.88 (d, J = 2.1 Hz, 1H), 6.84 (d, J = 4.2 Hz, 1H), 4.86 (br s, 2H), 4.12-4.06 (m, 2H), 2.88- 2.83 (m, 2H), 2.75-2.70 (m, 2H), 2.65-2.60 (m, 6H), 1.82-1.78 (m, 4H). MS (ESI): 369.2 (M+1). ESI-HRMS calcd for C ₂₀ H ₂₅ N ₄ SO (MH ⁺ ): 369.1743, observed: 369.173.

Example 7

1-(3-(Diethylamino)propyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one

1-(3-Chloropropyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (100 mg, 0.359 mmol), diethylamine (263 uL, 3.59 mmol), potassium iodide (596 mg, 3.59 mmol) and potassium carbonate (496 mg, 3.59 mmol) were weighed into an argon-vented vial equipped with a magnetic stir bar. Anhydrous acetonitrile (4 mL) was added and the yellow suspension was stirred at &lt When the starting material remained, the reaction was stirred at this temperature for an additional 3 days. After cooling to room temperature, the reaction was diluted with water (10 mL) and dichloromethane (15 mL) and transferred to a sep. The organic layer was collected, and the aqueous layer was extracted twice with dichloromethane (2×10 mL). The combined organic layers were washed with brine (15 mL) and dried over sodium sulfate. This solution was poured out and concentrated to give a yellow oil. The product was purified using flash chromatography (2M NH ₃ in _{MeOH: CH 2 Cl 2, 2.5-5} : 95-97.5) to give a yellow oil. Yield: 102 mg of yellow oil (93%). ¹ H NMR (CDCl ₃ ) δ: 8.14 (dd, J = 2.7, 9 Hz, 1H), 8.06 (d, J = 2.4 Hz, 1H), 7.23 (d, J = 9.0 Hz, 1H), 4.02 (t, J=7.5 Hz, 2H), 3.01 (t, J=7.2 Hz, 2H), 2.73-2.68 (m, 2H), 2.57-2.48 (m, 6H), 1.83-1.73 (m, 2H), 1.04 (t , J = 7.2 Hz, 6H). MS (EI): 305 (M+)

6-Amino-1-(3-diethylamino-propyl)-3,4-dihydro-1H-quinolin-2-one

1-(3-(Diethylamino)propyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (93 mg, 0.305 mmol) in anhydrous methanol (5 mL) Ni (water slurry, ~0.05 g) was treated with hydrazine hydrate (95 uL, 3.05 mmol) at room temperature and the mixture was refluxed for 30 min. The reaction was cooled to rt, filtered over EtOAc EtOAc (EtOAc) The combined methanol layer was evaporated and the crude product was purified by column chromatography to (2M NH ₃ in _{MeOH: CH 2 Cl 2, 2.5} : 97.5). Yield: 62 mg of yellow oil (74%). ¹ H NMR (CDCl ₃ ) δ: 6.87 (d, J = 8.4 Hz, 1H), 6.56 (dd, J = 2.7, 8.4 Hz, 1H), 6.52 (d, J = 2.1 Hz, 1H), 3.91 (m) , 2H), 2.81-2.76 (m, 2H), 2.61-2.54 (m, 2H), 2.52-2.46 (m, 6H), 1.78-1.61 (m, 2H), 1.01 (t, J = 7.2 Hz, 6H ). MS (ESI): 276.2 (M+1)

N-(1-(3-(diethylamino)propyl)-2-yloxy-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboxyindole Guanamine

6-Amino-1-(3-diethylamino-propyl)-3,4-dihydro-1H-quinolin-2-one (0.058 g, 0.211 mmol) in dry ethanol (5 mL) The solution was treated with methylthiophene-2-carbomine imine thiocarboxylate hydrogen iodide (0.120 g, 0.421 mmol) at room temperature, and the mixture obtained was stirred for 64 hr. The reaction was transferred to a sep. funnel and diluted with ethyl acetate (30 mL) and sat. The aqueous phase was further partitioned twice with ethyl acetate (2×20 mL). The combined organic phases were washed with brine and dried (Na ₂ SO _4). The solvent was evaporated and the crude material was purified eluting EtOAc EtOAc EtOAc Product 7 was dried under high vacuum. Yield: 35 mg of yellow solid (44%). ¹ H NMR (CDCl ₃ ) δ: 7.44 (d, J = 5.4 Hz, 1H), 7.41 (d, J = 3.3 Hz, 1H), 7.09 (t, J = 4.2 Hz, 1H), 7.06 (d, J) = 8.4 Hz, 1H), 6.88 (d, J = 2.1 Hz, 1H), 6.84 (d, J = 4.2 Hz, 1H), 4.90 (br s, 2H), 4.03 - 3.99 (m, 2H), 2.90 - 2.85 (m, 2H), 2.77-2.62 (m, 8H), 2.03-1.93 (m, 2H), 1.15 (t, J = 7.2 Hz, 6H). MS (ESI): 385.2 (M+1). ESI-HRMS calcd for C ₂₁ H ₂₉ N ₄ SO ₂ (MH ⁺ ): 385.2056, observed: 385.2040.

Example 8

6-nitro-1-(3-(pyrrolidin-1-yl)propyl)-3,4-dihydroquinoline -2(1H)-ketone

1-(3-Chloropropyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (100 mg, 0.359 mmol), pyrrolidine (300 uL, 3.59 mmol), potassium iodide (596 mg, 3.59 mmol) and potassium carbonate (496 mg, 3.59 mmol) were weighed into a vial ventilated with argon gas, and the vial was equipped with a magnetic stir bar. Anhydrous acetonitrile (4 mL) was added and the yellow suspension was stirred at &lt When the starting material remained, the reaction was stirred at this temperature for an additional 3 days. After cooling to room temperature, the reaction was diluted with water (10 mL) and dichloromethane (15 mL) and transferred to a sep. The organic layer was collected, and the aqueous layer was extracted twice with dichloromethane (2×10 mL). The combined organic phases were washed with brine (15 mL) and dried over sodium sulfate. This solution was poured out and concentrated to give a yellow oil. The product was purified using flash chromatography to give a yellow oil (2M NH ₃ in _{MeOH: CH 2 Cl 2, 2.5-5} : 95-97.5). Yield: 99 mg of yellow oil (91%). ¹ H NMR (CDCl ₃ ) δ: 8.13 (dd, J = 2.7, 9 Hz, 1H), 8.06 (d, J = 2.4 Hz, 1H), 7.23 (d, J = 9.0 Hz, 1H), 4.05 (t, J = 7.5 Hz, 2H), 3.00 (t, J = 7.2 Hz, 2H), 2.73 - 2.68 (m, 2H), 2.56 - 2.51 (m, 6H), 1.92-1.77 (m, 6H). MS (EI): 303 (M+)

6-Amino-1-(3-(pyrrolidin-1-yl)propyl)-3,4-dihydroquinolin-2(1H)-one

6-Nitro-1-(3-(pyrrolidin-1-yl)propyl)-3,4-dihydroquinolin-2(1H)-one (89 mg, 0.293 mmol) in dry methanol (5 mL) Treated with Ra-Ni (~0.05 g) and treated with hydrazine hydrate (92 uL, 2.95 mmol) at room temperature and the mixture was refluxed for 30 min. The reaction was cooled to rt, filtered over EtOAc EtOAc (EtOAc) The combined methanol layer was evaporated and the crude product was purified by column chromatography to (2M NH ₃ in _{MeOH: CH 2 Cl 2, 2.5} : 97.5). Yield: 58 mg of yellow oil (73%). ¹ H NMR (CDCl ₃ ) δ: 6.86 (d, J = 8.4 Hz, 1H), 6.55 (dd, J = 2.7, 8.4 Hz, 1H), 6.52 (d, J = 2.1 Hz, 1H), 3.94 (m) , 2H), 2.81-2.76 (m, 2H), 2.61-2.56 (m, 2H), 2.53-2.49 (m, 6H), 1.87-1.82 (m, 2H), 1.79-1.75 (m, 4H). MS (ESI): 274.2 (M+1)

N-(1-(3-(pyrrolidin-1-yl)propyl)-2-yloxy-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboxyindole Amine

6-Amino-1-(3-(pyrrolidin-1-yl)propyl)-3,4-dihydroquinolin-2(1H)-one (0.053 g, 0.194 mmol) in dry ethanol (5 mL) The solution was treated with methylthiophene-2-carbomine imine thiocarboxylate hydrogen iodide (0.110 g, 0.386 mmol) at room temperature, and the resulting mixture was stirred for 64 hours. The reaction was transferred to a sep. funnel and diluted with ethyl acetate (30 mL) and sat. The aqueous phase was further partitioned twice with ethyl acetate (2×20 mL). The combined organic phases were washed with brine and dried (Na ₂ SO _4). The solvent was evaporated and the crude material was purified eluting EtOAc EtOAc EtOAc The product was dried under high vacuum. Yield: 31 mg of yellow solid (42%). ¹ H NMR (CDCl 3 ) δ: 7.44 (d, J = 5.4 Hz, 1H), 7.41 (d, J = 3.3 Hz, 1H), 7.09 (t, J = 4.2 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.88 (d, J = 2.1 Hz, 1H), 6.84 (d, J = 4.2 Hz, 1H), 4.91 (br s, 2H), 4.05 - 4.00 (m, 2H), 2.89 - 2.85 (m, 2H), 2.70-2.64 (m, 8H), 2.02-1.97 (m, 2H), 1.90 to 1.82 (m, 4H). MS (ESI): 383.2 (M+1). ESI-HRMS calcd for C ₂₁ H ₂₇ N ₄ SO ₂ (MH ⁺ ): 383.1900, observed: 383.1895.

Example 9

6-nitro-1-(3-(piperidin-1-yl)propyl)-3,4-dihydroquinolin-2(1H)-one

1-(3-Chloropropyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (100 mg, 0.359 mmol), piperidine (355 uL, 3.59 mmol), potassium iodide (596 mg) , 3.59 mmol) and potassium carbonate (496 mg, 3.59 mmol) were weighed into a vial ventilated with argon gas, and the vial was equipped with a magnetic stir bar. Anhydrous acetonitrile (4 mL) was added and the yellow suspension was stirred at &lt When the starting material remained, the reaction was stirred at this temperature for an additional 3 days. After cooling to room temperature, the reaction was diluted with water (10 mL) and dichloromethane (15 mL) and transferred to a sep. The organic layer was collected, and the aqueous layer was extracted twice with dichloromethane (2×10 mL). The combined organic portions were washed with brine (15 mL) and dried over sodium sulfate. This solution was poured out and concentrated to give a yellow oil. The product was purified using flash chromatography (2M NH ₃ in _{MeOH: CH 2 Cl 2, 2.5-5} : 95-97.5) to give a yellow oil. Yield: 102 mg of yellow oil (89%). ¹ H NMR (CDCl ₃ ) δ: 8.13 (dd, J = 2.7, 9 Hz, 1H), 8.05 (d, J = 2.4 Hz, 1H), 7.29 (d, J = 9.0 Hz, 1H), 4.02 (t, J=7.5 Hz, 2H), 3.00 (t, J=7.2 Hz, 2H), 2.73-2.68 (m, 2H), 2.39-2.35 (m, 6H), 1.88-1.79 (m, 2H), 1.64-1.45 (m, 6H). MS (EI): 317 (M+)

6-Amino-1-(3-(piperidin-1-yl)propyl)-3,4-dihydroquinolin-2(1H)-one

6-Nitro-1-(3-(piperidin-1-yl)propyl)-3,4-dihydroquinolin-2(1H)-one (98 mg, 0.309 mmol) in anhydrous methanol (5 mL) Treated with Ra-Ni (~0.05 g of water in water), treated with hydrazine hydrate (96 uL, 3.08 mmol) at room temperature, and the mixture was refluxed for 30 minutes. The reaction was cooled to rt, filtered over EtOAc EtOAc (EtOAc) The combined methanol layer was evaporated and the crude product was purified by column chromatography to (2M NH ₃ in _{MeOH: CH 2 Cl 2, 2.5} : 97.5). Yield: 71 mg of yellow oil (80%). ¹ H NMR (CDCl ₃ ) δ: 6.90 (d, J = 8.4 Hz, 1H), 6.55 (dd, J = 2.7, 8.4 Hz, 1H), 6.51 (d, J = 2.1 Hz, 1H), 3.91 (m) , 2H), 2.80-2.76 (m, 2H), 2.61-2.56 (m, 2H), 2.38-2.33 (m, 6H), 1.84-1.79 (m, 2H), 1.60-1.55 (m, 4H), 1.46 -1.42 (m, 2H). MS (ESI): 288.2 (M+1).

N-(1-(3-(piperidin-1-yl)propyl)-2-yloxy-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboxyindole Amine

6-Amino-1-(3-(piperidin-1-yl)propyl)-3,4-dihydroquinolin-2(1H)-one (0.065 g, 0.226 mmol) in dry ethanol (5 mL The solution was treated with methylthiophene-2-carbomine imine thiocarboxylate hydrogen iodide (0.129 g, 0.452 mmol) at room temperature, and the mixture obtained was stirred for 64 hr. The reaction was transferred to a sep. funnel and diluted with ethyl acetate (30 mL) and sat. The aqueous phase was further partitioned twice with ethyl acetate (2×20 mL). The combined organic phases were washed with brine and dried (Na ₂ SO _4). The solvent was evaporated and the crude material was purified eluting EtOAc EtOAc EtOAc The product was dried under high vacuum. Yield: 46 mg of yellow solid (51%). ¹ H NMR (DMSO- d ₆ ) δ: 8.02 (d, J = 3.9 Hz, 1H), 7.99 (d, J = 3 Hz, 1H), 7.32 (d, J = 4.8 Hz, 1H), 7.28 (d, J=6.3 Hz, 1H), 7.20 (s, 1H), 7.17 (s, 1H), 4.32 (br s, 2H), 3.98-3.93 (m, 2H), 3.45-3.40 (m, 4H), 3.16- 3.10 (m, 4H), 2.95-2.90 (m, 4H), 2.61-2.56 (m, 2H), 2.01-1.90 (m, 2H). MS (ESI): 397.2 (M+1). ESI-HRMS calcd for _{C 22 H 29 N 4 SO (} MH +): 397.2056, observed: 397.2073.

Example 10:

1-(4-methoxybenzyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one

6-Nitro-3,4-dihydroquinolin-2(1H)-one (500 mg, 2.60 mmol), 4-methoxybenzyl chloride (388 μL, 2.86 mmol) and potassium carbonate (1.08 g, 7.80) A suspension of 10 mL of DMF was stirred at room temperature overnight. Thereafter, the mixture was poured into 20 mL of H ₂ O and then extracted with 2×50 mL of CH ₂ Cl ₂ . The organic layer was separated, washed with brine and concentrated to give a yellow solid which was subjected to flash chromatography on silica using 1% MeOH / CH ₂ Cl ₂ to give an off-white solid (605mg, 74.5%). ¹ H-NMR (DMSO-d ₆ ) δ: 8.15 (d, J = 2.7 Hz, 1H), 8.02 (dd, J = 2.7, 9.0 Hz, 1H), 7.15 (dd, J = 3.0, 9.0 Hz, 1H) ), 6.88-6.85 (m, 4H), 5.14 (s, 2H), 3.70 (s, 3H), 3.11-3.06 (m, 2H), 2.80-2.75 (m, 2H).

MS (EI): 312.4 (M ⁺ , 10%), 121.3 (100%).

3-(3-chloropropyl)-1-(4-methoxybenzyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one

A solution of 1-(4-methoxybenzyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (350 mg, 1.12 mmol) in 10 mL THF cooled to -78. (Acetone/dry ice bath) then lithium hexamethyldiamine (1.23 mL of 1 M solution in THF). The resulting dark solution was stirred for 30 minutes and then added dropwise with 1-iodo-3-chloropropane. The mixture was allowed to warm to room temperature and maintained at this temperature overnight. The reaction was quenched with brine and extracted with concentrated to 3 × 50mL CH ₂ Cl _2. The combined organic portion over magnesium sulfate, filtered and concentrated to give a dark residue which was subjected to flash chromatography on silica, using CH ₂ Cl _2. A yellow viscous oil (130 mg, 29.8%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 8.08-8.00 (m, 2H), 7.12-7.09 (m, 2H), 7.00 (d, J = 8.7 Hz, 1H), 6.86-6.84 (m, 2H), 5.15 (dd, J=4.2, 20.4 Hz, 2H), 3.76 (s, 3H), 3.60 (t, J = 6.3 Hz, 2H), 3.17 (dd, J = 5.4, 15.6 Hz, 1H), 2.93 - 2.71 ( m, 2H), 2.05-1.67 (m, 4H).

MS (EI): 388 (M ⁺ , 10%), 121.3 (100%).

3-(3-(Dimethylamino)propyl)-1-(4-methoxybenzyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one

3-(3-Chloropropyl)-1-(4-methoxybenzyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (120 mg, 0.31 mmol), A suspension of sodium iodide (47 mg, 0.31 mmol) and potassium carbonate in 3 mL of EtOAc was treated with dimethylamine in THF (0.3 mL 2M solution, 0.62 mmol). The mixture was heated at 80 ° C for 22 hours in a sealed tube. The reaction was cooled to room temperature and then filtered through a pad of Celite. The filter pad was rinsed with methanol and the filtrate was concentrated to give a brown residue which was used without further purification. Yield: 115 mg (93.5%). ¹ H-NMR (CDCl ₃ ) δ: 8.07 (d, J = 2.4 Hz, 1H), 8.00 (dd, J = 2.7, 9 Hz, 1H), 7.11-7.08 (m, 2H), 6.98 (d, J = 9.0 Hz, 1H), 6.87-6.84 (m, 2H), 5.15 (dd, J = 4.2, 20.4 Hz, 2H), 3.76 (s, 3H), 3.15 (dd, J = 5.4, 15.6 Hz, 1H), 2.95-2.87 (m, 4H), 2.48 (s, 6H), 1.92-1.61 (m, 4H).

MS (ESI): 398.2 (MH ⁺ , 100%)

6-Amino-3-(3-(dimethylamino)propyl)-1-(4-methoxybenzyl)-3,4-dihydroquinolin-2(1H)-one

3-(3-(Dimethylamino)propyl)-1-(4-methoxybenzyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one ( A solution of 115 mg, 0.29 mmol) in 10 mL of methanol was added to Raney Nickel (yield in water, 50 mg) in a round bottom flask. This suspension was treated with hydrazine hydrate (90 [mu]L, 2.90 mmol) and heated to reflux for 10 min then filtered over a pad. The diatomaceous earth pad was rinsed with 10 mL of methanol. The filtrate was concentrated to give a yellow residue which was subjected to flash silica gel chromatography using 5% 2M NH ₃ in MeOH / CH ₂ Cl ₂ to give a yellow semi-solid (77mg, 72.3%). ¹ H-NMR (CDCl ₃ ) δ: 7.13-7.10 (m, 2H), 6.83-6.80 (m, 2H), 6.69 (d, J = 8.4 Hz, 1H), 6.50 (d, J = 2.4 Hz, 1H) ), 6.42 (dd, J = 2.4, 8.4 Hz, 1H), 5.05 (dd, J = 15.6, 29.1 Hz, 2H), 3.76 (s, 3H), 3.48 (br s, 2H), 3.01-2.91 (m , 1H), 2.70-2.58 (m, 2H), 2.28 (t, J = 7.2 Hz, 2H), 2.21 (s, 6H), 1.88-1.42 (m, 4H). MS (ESI): 368.2 (MH ⁺ , 100%)

N-(3-(3-(Dimethylamino)propyl)-1-(4-methoxybenzyl)-2-oxooxy-1,2,3,4-tetrahydroquinoline- 6-yl)thiophene-2-carboxyindoleimine

6-Amino-3-(3-(dimethylamino)propyl)-1-(4-methoxybenzyl)-3,4-dihydroquinolin-2(1H)-one (70 mg , a solution of 0.19 mmol) in 5 mL of EtOAc (EtOAc) (EtOAc) This mixture was argon into the pump for 20 minutes then layered Room in CH ₂ Cl ₂ (50mL) and saturated sodium bicarbonate (10mL). The aqueous layer was an additional 20mL CH ₂ Cl ₂ extracted with. The combined organic layers were washed with concentrated brine, dried over sodium sulfate and concentrated to give a yellow residue which was subjected to flash chromatography on silica using _2% MeOH / CH 2 Cl 2 followed by 5% 2M NH ₃ in MeOH / CH ₂ Cl ₂ gave a pale yellow solid (70 mg, 77.7%). An HPLC analysis showed the product to be >99% pure. ¹ H-NMR (DMSO-d ₆ ) δ: 7.71 (d, J = 3.6 Hz, 1H), 7.58 (d, J = 5.1 Hz, 1H), 7.16 (d, J = 8.7 Hz, 2H), 7.08 ( t, J = 3.9, 1H), 6.89-6.86 (m, 3H), 6.75 (br s, 1H), 6.64 - 6.62 (m, 1H), 6.46 (br s, 2H), 5.03 (dd, J = 15.9) , 5.1 Hz, 2H), 3.71 (s, 3H), 3.00 (dd, J = 5.1, 15.2 Hz, 1H), 2.73 - 2.56 (m, 2H), 2.22 (t, J = 6.6 Hz, 2H), 2.14 (s, 6H), 1.78-1.34 (m, 4H). MS (ESI): 477.2 (M+1).

N-(3-(3-(Dimethylamino)propyl)-2-yloxy-1,2,3,4-tetrahydroquine Phenyl-6-yl)thiophene-2-carboxyindoleimine guanamine dihydrogen chloride

N-(3-(3-(Dimethylamino)propyl)-1-(4-methoxybenzyl)-2-oxoyl-1,2,3,4-tetrahydroquinoline -6-yl) thiophene-2-carboxyindoleimine (50 mg, 0.1 mmol) and anisole (23 μL, 0.2 mmol) in 7.5 mL of trifluoroacetic acid, stirred at room temperature for 2 hours, then at 60 ° C Heat for 22 hours. TLC analysis showed that only the starting material was present. The mixture was concentrated and treated with 3N HCl & EtOAc (5 mL) and then warm. The yellow solution was treated with saturated NaHCO ₃ then extracted with 3 × 20mL CH ₂ Cl _2. The combined organic layers were dried over MgSO _4, filtered and concentrated to give a yellow residue. The residue was subjected to flash chromatography on silica, using 5% 2M NH ₃ in MeOH / CH ₂ Cl ₂ to give a pale yellow solid. This compound was dissolved in CH ₂ Cl ₂ (5mL), and to a solution of 1M HCl 1mL treated in Et ₂ O, to form a precipitate. The syrup was concentrated to give a yellow solid (22 mg, 51.3%). An HPLC analysis showed the product to be >99% pure. ¹ H-NMR (CD ₃ OD) δ: 7.96-7.95 (d, J = 4.5 Hz, 2H), 7.31 (pseudo t, J = 4.2 Hz, 1H), 7.24 (br s, 1H), 7.17 (dd, J=1.5, 8.1 Hz, 1H), 7.00 (d, J=5.9 Hz, 1H), 3.17-3.10 (m, 2H), 2.85 (s, 6H), 2.91-2.83 (m, 2H) 2.67-2.60 ( m, 1H), 1.91-1.56 (m, 4H)

MS (ESI): 357.2 (M+1). ESI-HRMS calcd for C ₁₉ H ₂₄ N ₄ SO (MH ⁺ ): 357.1743, observed: 357.1744.

Example 11

1-(2-(Dimethylamino)ethyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one

6-Nitro-3,4-dihydroquinolin-2(1H)-one (1.5 g, 7.80 mmol), 2-chloro-N,N-dimethylethylamine hydrogen chloride (2.25 g, 15.60 mmol) A suspension of potassium carbonate (6.47 g, 46.80 mmol) in 25 mL of DMF was stirred at room temperature for 3 days. After the mixture was poured into 20mL H ₂ O 150 mL then extracted with EtOAc in ×. 3. The combined organic portions were washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was subjected to flash chromatography on silica gel using 5% 2M NH ₃ in MeOH / CH ₂ Cl ₂ to give a viscous yellow oil (1.5g, 73.2%). ¹ H-NMR (CDCl ₃ ) δ: 8.14 (dd, J = 2.4, 9.0 Hz, 1H), 8.06 (d, J = 2.4 Hz, 1H), 7.15 (d, J = 9.0 Hz, 1H), 4.09 ( t, J = 7.5 Hz, 2H), 3.03 - 2.98 (m, 2H), 2.73 - 2.68 (m, 2H), 2.51 (t, J = 7.5 Hz, 2H), 2.31 (s, 6H).

6-Amino-1-(2-(dimethylamino)ethyl)-3,4-dihydroquinolin-2(1H)-one

1-(2-(Dimethylamino)ethyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (1.48 g, 5.62 mmol) and palladium on activated carbon A suspension of (10%, 300 mg, 0.28 mmol) in 20 mL of ethanol was stirred overnight in a hydrogen atmosphere. This suspension was filtered through a pad of celite. The filter pad was rinsed with 50 mL of ethanol and the filtrate was concentrated to give a viscous oil. This crude product was used without further purification. (1.3g, 100%). ¹ H-NMR (CDCl ₃ ) δ: 6.85 (d, J = 8.7 Hz, 1H), 6.55 (dd, J = 2.7, 8.7 Hz, 1H), 6.51 (d, J = 2.7 Hz, 1H), 4.00 ( t, J=7.5 Hz, 2H), 3.56 (br s, 2H), 2.80-2.75 (m, 2H), 2.60-2.55 (m, 2H), 2.47 (t, J = 7.5 Hz, 2H), 2.31 ( s, 6H).

1-(2-(Dimethylamino)ethyl)-0,2,3,4-tetrahydroquinolin-6-amine

A solution of 6-amino-1-(2-(dimethylamino)ethyl)-3,4-dihydroquinolin-2(1H)-one (1.3 g, 5.57 mmol) in 10 mL anhydrous THF was added dropwise to a cooled 1M LiAlH ₄ in THF (22.3mL, 22.3mmol) of the suspension. The suspension was stirred at room temperature for 1 day. The mixture was then cooled to 0 ° C and added dropwise with 5 mL of 1N NaOH while stirring rapidly. After stirring for 30 minutes, this suspension was Na ₂ SO ₄ and filtered. The filter cake at 10% 2M NH ₃ in MeOH / CH ₂ Cl ₂ (100mL total) rinse. The filtrate was concentrated and the dark residue was applied to flash chromatography on silica using 5-10% 2M NH ₃ in MeOH / CH ₂ Cl ₂ to give a dark viscous oil (930mg, 76.2%). ¹ H-NMR (CDCl ₃ ) δ: 6.49 (brs, 2H), 6.40 (s, 1H), 3.34-3.30 (m, 2H), 3.30 (br s, 2H), 3.21. (t, J = 5.7 Hz, 2H), 2.68 (t, J = 5.7 Hz, 2H), 2.49-2.44 (m, 2H), 2.28 (s, 6H), 1.95-1.87 (m, 2H).

MS (ESI): 220.2 (m+1).

N-(1-(2-(Dimethylamino)ethyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboxyindoleimine

A solution of 1-(2-(dimethylamino)ethyl)-1,2,3,4-tetrahydroquinolin-6-amine (900 mg, 4.10 mmol) in 25 mL of EtOH with methylthiophene- Treatment with 2-carboquinone thiocarboxylate hydrogen iodide (2.34 g, 1.43 mmol) and stirring at rt overnight. This mixture was argon into the pump for 20 minutes then layered Room in CH ₂ Cl ₂ (100 mL) and saturated sodium bicarbonate (20mL). The additional organic layer was separated and extracted the aqueous layer 50mL CH ₂ Cl _2. The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated to give a dark oil, which was applied to silica gel eluting with 5% MeOH/CH ₂ Cl ₂ followed by 5% 2M NH ₃ MeOH / CH ₂ Cl ₂ to give an orange solid ^{_{1 H-NMR (DMSO- d 6}} ) δ: 7.66 (d, J = 3.6Hz, 1H), 7.55 (d, J = 4.8Hz, 1H), 7.08-7.05 (m, 1H), 6.57-6.48 (m, 3H), 6.25 (brs, 2H), 3.29-3.21 (m, 4H), 2.65 (t, J = 6.3 Hz, 2H), 2.39 (t, J = 6.3) Hz, 2H), 2.19 (s, 6H), 1.85-1.82 (m, 2H).

MS (ESI): 329.2 (M+1). ESI-HRMS calculated for C ₁₈ H ₂₄ N ₄ S (MH ⁺ ): 329.1794, observed: 329.1804.

Example 12.

1-(2-(pyrrolidin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one

3,4-Dihydroquinolin-2(1H)-one (1.0 g, 6.79 mmol), 1-(2-chloroethyl)pyrrolidinium chloride (1.27 g, 7.47 mmol) and potassium carbonate (2.82 g, A suspension of 20.37 mmol) in 10 mL of DMF was stirred at room temperature overnight and then heated to 95 ° C for 1 day. After the mixture was poured into 20mL H ₂ O and extracted with 2 × 100mL EtOAc. The combined organic portions were washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was dried under reduced pressure for 18 hours and then applied to a silica gel using 5% MeOH/CH ₂ Cl ₂ followed by 5% 2M NH ₃ in MeOH / CH ₂ Cl ₂ to give a yellow viscous oil (800 mg , 48.2%). ¹ H-NMR (CDCl ₃ ) δ: 7.24 - 7.08 (m, 3H), 7.00 (m, 1H), 4.10 (t, J = 7.8 Hz, 2H), 2.89 (psuedo t, J = 6.7 Hz, 2H) , 2.74-2.60 (m, 8H), 1.82-1.78 (m, 4H).

MS (ESI): 245.2 (M+1).

1-(2-(pyrrolidin-1-yl)ethyl)-1,2,3,4-tetrahydroquinoline

1- (2- (pyrrolidin-1-yl) ethyl) -3,4-dihydro-quinolin -2 (1H) - one (700mg, 2.87mmol) in 12mL of dry THF was treated with LiAlH ₄ ( 218 mg, 5.73 mmol) was processed in divided portions. The suspension was stirred at room temperature for 1 day. The mixture was then cooled to 0 ° C and added dropwise with 2 mL of 1N NaOH while stirring rapidly. After stirring for 30 minutes, this suspension was Na ₂ SO ₄ and filtered. The filter cake was rinsed with CH ₂ Cl ₂ (total 150mL). The filtrate was concentrated and the residue was subjected to flash chromatography on silica gel using 5% 2M NH ₃ in MeOH / CH ₂ Cl ₂ to give a pale yellow oil (563mg, 85.1%). ¹ H-NMR (CDCl ₃ ) δ: 7.06-7.01 (m, 1H), 6.93 (d, J = 7.2 Hz, 1H), 6.63-6.52 (m, 2H), 3.44 (t, J = 7.5 Hz, 2H) ), 3.31 (t, J = 5.7 Hz, 2H), 2.76-2.56 (m, 8H), 1.97-1.90 (m, 2H), 1.83-1.78 (m, 4H).

MS (ESI): 231.2 (M+1, 100%).

6-bromo-1-(2-(pyrrolidin-1-yl)ethyl)-1,2,3,4-tetrahydroquinoline

1-(2-(Pyrrolidin-1-yl)ethyl)-1,2,3,4-tetrahydroquinoline (490 mg, 2.13 mmol) in 10 mL of carbon tetrachloride, cooled to 0 ° C, It was then treated in portions with NBS (378 mg, 2.13 mmol). The resulting suspension was stirred at 0 ° C for 3.5 hours. The mixture was filtered through celite and the pad was washed with 3×20 mL hexane. The filtrate was concentrated to give a light brown residue, which was subjected to flash chromatography on silica, using 5% 2M NH ₃ in MeOH / CH ₂ Cl ₂ to give a light brown oil ^{(380mg, 57.7%) 1 H} -NMR (CDCl ₃ ) δ: 7.09 (dd, J = 2.4, 8.7 Hz, 1H), 7.02 (d, J = 2.4 Hz, 1H), 6.46 (d, J = 8.7 Hz, IH), 3.42 (t, J = 7.8 Hz, 2H), 3.29 (t, J = 5.7 Hz, 2H), 2.76-2.55 (m, 8H), 1.95-1.89 (m, 2H), 1.82-1.77 (m, 4H).

MS (ESI): 309.1 and 311.1 (M+1, 100%).

1-(2-(pyrrolidin-1-yl)ethyl)-1,2,3,4-tetrahydroquinolin-6-amine

6-Bromo-1-(2-(pyrrolidin-1-yl)ethyl)-1,2,3,4-tetrahydroquinoline (355 mg, 1.15 mmol) and Pd ₂ (dba) ₃ (52 mg, 0.12 mmol) in 10mL of dry THF was treated with hexamethyl disilazane silicon lithium (2.3 mL of 1M solution in THF, 2.3 mmol) process, then PtBu ₃ (700μL of 10% wt solution in hexane, 0.23mmol )deal with. The dark brown suspension obtained was heated at 90 °C for 2 hours. The mixture was cooled to room temperature and 7ml of a 1N HCl solution and then stirred at room temperature for 15 minutes and this mixture between _{1N NaOH CH 2 Cl 2 (100mL} ) (20mL) delamination. The organic layer was separated and the aqueous layer again with 100mL CH ₂ Cl ₂ extracted once. The combined organic portions were washed with brine, dried over sodium sulfate, dried &lt The residue was subjected to flash chromatography on silica, using 5% MeOH / CH ₂ Cl ₂ then 5-10% 2M NH ₃ in MeOH / CH ₂ Cl ₂ to give a viscous dark brown residue (180mg, 63.8%). ¹ H-NMR (CDCl ₃ ) δ: 6.53-6.49 (m, 2H), 6.40 (br s, 1H), 3.37 (t, J = 7.5 Hz, 2H), 3.21 (br s, 2H), 3.20 (t , J=5.4 Hz, 2H), 2.70-2.66 (m, 4H), 2.63-2.55 (m, 4H), 1.95-1.86 (m, 2H), 1.81-1.77 (m, 4H).

MS (ESI): 246.2 (M+1)

N-(1-(2-(2-(pyrrolidin-1-yl)ethyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboxyindoleimine guanamine dihydrogen chloride

a solution of 1-(2-(pyrrolidin-1-yl)ethyl)-1,2,3,4-tetrahydroquinolin-6-amine (175 mg, 0.71 mmol) in 10 mL of EtOH as methylthiophene Treatment with 2-carboquinone thiocarboxylate hydrogen iodide (407 mg, 1.43 mmol) and stirring at room temperature overnight. This mixture was argon into the pump for 20 minutes then layered Room in CH ₂ Cl ₂ (100 mL) and saturated sodium bicarbonate (20mL). The aqueous layer was an additional 50mL CH ₂ Cl ₂ extracted with. The combined organic layers were washed with concentrated brine, dried over sodium sulfate and concentrated to give a dark oil, which was subjected to flash chromatography on silica, using _{5% MeOH / CH 2 Cl 2} , followed by 5-10% 2M NH ₃ in MeOH/CH ₂ Cl ₂ to give a dark brown residue. This compound was dissolved (185 mg) in CH ₂ Cl ₂ (5mL), and to 2mL of 1M HCl in Et2O treated to form a precipitate. The suspension was diluted with hexane (15 mL) and the solid was filtered. The solid was hygroscopic, so it was dissolved in methanol (10 mL), concentrated and concentrated under reduced pressure. A greenish yellow solid 12 (230 mg, 75.9%) was obtained. An HPLC analysis showed the product to be >99% pure. ¹ H-NMR (CD ₃ OD) δ: 8.03 - 8.00 (m, 2H), 7.36-7.33 (m, 1H), 7.10 (dd, J = 2.7, 8.7 Hz, 1H), 7.01 (d, J = 2.7 Hz, 1H), 6.89 (d, J = 8.7 Hz, 1H), 3.78-3.71 (m, 4H), 3.4-3.39 (m, 4H), 3.21-3.13 (m, 2H), 2.81 (t, J = 6.3 Hz, 2H), 2.20.19.96 (m, 6H)

MS (ESI): 355.2 (M+1). ESI-HRMS calculated for C ₂₀ H ₂₇ N ₄ S ₁ (MH ⁺ ): 355.1950, observed: 355.1945.

Example 13

1-(2-(1-methylpyrrolidin-2-yl)ethyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one

6-Nitro-3,4-dihydroquinolin-2(1H)-one (2.0 g, 10.4 mmol), 2-(2-chloroethyl)-1-methylpyrroleidine hydrogen chloride (3.83 g, 20.8 A suspension of sodium iodide (779 mg, 5.20 mmol) and potassium carbonate (8.63 g, 62.4 mmol) in dimethylformamide (15 mL) was stirred at room temperature overnight. After this time the mixture was diluted with water (15 mL) then ethyl acetate (3×75 mL). The combined organic portions were washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was subjected to flash chromatography on silica gel using 5% 2M NH ₃ in MeOH / CH ₂ Cl ₂ to give an orange oil, under reduced pressure to dryness (2.32g, 73.7%). ¹ H-NMR (CDCl ₃ ) δ: 8.13 (dd, J = 2.7, 9 Hz, 1H), 8.05 (d, J = 2.4 Hz, 1H), 7.11 (d, J = 9.0 Hz, 1H), 4.15 - 4.05 (m, 1H), 3.97-3.87 (m, 1H), 3.05-3.01 (m, 4H), 2.72-2.70 (m, 2H), 2.28 (s, 3H), 2.17- 1.60 (m, 7H)

MS (EI): 303 (M+).

6-Amino-1-(2-(1-methylpyrrolidin-2-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one

1-(2-(1-Methylpyrrolidin-2-yl)ethyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (2.25 g, 7.42 mmol) A suspension of palladium on activated carbon (10%, 100 mg, 0.09 mmol) in 50 mL of ethanol was stirred in a hydrogen balloon for 2 days. This suspension was filtered through a pad of celite. The filter pad was rinsed with 50 mL of ethanol and the filtrate was concentrated to give a viscous oil. The crude product was subjected to Biotage flash chromatography on silica, using 0-5% 2M NH ₃ in MeOH / CH ₂ Cl ₂ to give a yellow foam (1.48g, 72.9%). ¹ H-NMR (CDCl ₃ ) δ: 6.82 (d, J = 8.4 Hz, 1H), 6.55 (dd, J = 3.0, 8.4 Hz, 1H), 6.52 (d, J = 3.0 Hz, 1H), 4.09- 3.99 (m, 1H), 3.86-3.76 (m, 1H), 3.54 (br s, 2H), 3.04-3.01 (m, 1H), 2.81-2.76 (m, 2H), 2.61-2.56 (m, 2H) , 2.29(s,3H),2.17-1.60(m,8H)

MS (ESI): 274.2 (M+1, 100%).

N-(1-(2-(1-methylpyrrolidin-2-yl)ethyl)-2-yloxy-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2 - Carboxylimine amide

6-Amino-1-(2-(1-methylpyrrolidin-2-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one (1.15 g, 4.21 mmol) A solution of absolute ethanol (25 mL) was taken from EtOAc (EtOAc m. The reaction was diluted with diethyl ether (150 mL) and the precipitate was collected in vacuo. The precipitate was washed with ether (50 mL). The yellow solid was dissolved in water (50 mL) and transferred to a sep. funnel. The reaction was treated with 1N EtOAc (10 mL)EtOAcEtOAc The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to give a yellow oil which was subjected to flash chromatography on silica, using 0-5% 2M NH ₃ in MeOH / CH ₂ Cl ₂ to Get a yellow bubble. Yield: 1.11 g of yellow foam (69%). ¹ H-NMR (DMSO-d ₆ ) δ: 7.73 (d, J = 3.0 Hz, 1H), 7.60 (d, J = 5.4 Hz, 1H), 7.10-7.02 (m, 2H), 6.72-6.75 (m, 2H), 6.45 (br s, 2H), 3.91-3.80 (m, 2H), 2.96-2.90 (m, 1H), 2.82-2.78 (m, 2H), 2.19(s,3H), 2.08-1.80(m,6H),1.66-1.49(m,4H)

MS (ESI): 383.2 (M+1). ESI-HRMS calcd for C ₂₁ H ₂₇ N ₄ OS (MH ⁺ ): 383.1900. observed: 383.1902.

Example 14

1-(2-(1-methylpyrrolidin-2-yl)ethyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one

6-Nitro-3,4-dihydroquinolin-2(1H)-one (2.0 g, 10.4 mmol), 2-(2-chloroethyl)-1-methylpyrrolidinium chloride (3.83 g, A suspension of 20.8 mmol), sodium iodide (779 mg, 5.20 mmol) and potassium carbonate (8.63 g, 62.4 mmol) in 15 mL of DMF was stirred at room temperature overnight. After the mixture was poured into 50mL H ₂ O and extracted with 2 × 100mL EtOAc. The combined organic portions were washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was dried under reduced pressure for 18 hours and then subjected to flash chromatography on silica, using 5% MeOH / CH ₂ Cl ₂ followed by 5% 2M NH ₃ in MeOH / CH ₂ Cl ₂ to give an orange oil, in reducing Dry curing (2.32 g, 73.7%) by pressing. ¹ H-NMR (CDCl ₃ ) δ: 8.13 (dd, J = 2.7, 9 Hz, 1H), 8.05 (d, J = 2.4 Hz, 1H), 7.11 (d, J = 9.0 Hz, 1H), 4.15 - 4.05 (m, 1H), 3.97-3.87 (m, 1H), 3.05-3.01 (m, 4H), 2.72-2.70 (m, 2H), 2.28 (s, 3H), 2.17- 1.60 (m, 7H)

MS (EI): 303 (M+).

6-Amino-1-(2-(1-methylpyrrolidin-2-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one

1-(2-(1-Methylpyrrolidin-2-yl)ethyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (2.25 g, 7.42 mmol) A suspension of palladium on activated carbon (10%, 100 mg, 0.09 mmol) in 50 mL of ethanol was stirred in a hydrogen balloon for 2 days. This suspension was filtered through a pad of celite. The filter pad was rinsed with 50 mL of ethanol and the filtrate was concentrated to give a viscous oil. The crude product was subjected to Biotage flash chromatography on silica, using 0-5% 2M NH ₃ in MeOH / CH ₂ Cl ₂ to give a yellow foam (1.48g, 72.9%). ¹ H-NMR (CDCl ₃ ) δ: 6.82 (d, J = 8.4 Hz, 1H), 6.55 (dd, J = 3.0, 8.4 Hz, 1H), 6.52 (d, J = 3.0 Hz, 1H), 4.09- 3.99 (m, 1H), 3.86-3.76 (m, 1H), 3.54 (br s, 2H), 3.04-3.01 (m, 1H), 2.81-2.76 (m, 2H), 2.61-2.56 (m, 2H) , 2.29(s,3H),2.17-1.60(m,8H)

MS (ESI): 274.2 (M+1, 100%).

1-(2-(1-methylpyrrolidin-2-yl)ethyl)-1,2,3,4-tetrahydroquinolin-6-amine

6-Amino-1-(2-(1-methylpyrrolidin-2-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one (1H)-one (350 mg, 1.28 mmol) in 5mL of dry THF was added dropwise to the cooled 1M LiAlH ₄ in THF (5.1mL, 5.1mmol) of the suspension. The suspension was stirred at room temperature for 1 day. The mixture was then cooled to 0 ° C and treated dropwise with 1 mL of 1N NaOH while stirring rapidly. After stirring for 30 minutes, the suspension was treated in a Na ₂ SO ₄ to 20mL 10% 2M NH ₃ in MeOH / CH Cl _{2 diluted} and filtered. The filter cake was washed 50mL10% 2M NH ₃ in MeOH / CH ₂ Cl ₂ rinse. The filtrate was concentrated and the dark residue was applied to flash chromatography on silica using 5-10% 2M NH ₃ in MeOH / CH ₂ Cl ₂ to give a dark viscous oil (172mg, 52.0%). ¹ H-NMR (CDCl ₃ ) δ 6.48 (brs, 2H), 6.41 (brs, 1H), 3.29-3.03 (m, 8H), 2.68 (t, J = 6.6 Hz, 2H), 2.30 (s, 3H) , 2.18-1.42 (m, 9H)

MS (ESI): 260.2 (M+1, 100%).

N-(1-(2-(1-methylpyrrolidin-2-yl)ethyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboxyindoleimine amine

a solution of 1-(2-(1-methylpyrrolidin-2-yl)ethyl)-1,2,3,4-tetrahydroquinolin-6-amine (160 mg, 0.61 mmol) in 10 mL EtOAc. Treated with methylthiophene-2-carbomine thiocarboxylate hydrogen iodide (353 mg, 1.24 mmol) and stirred at room temperature for 2 days. Argon enters the pump the mixture for 30 minutes and then layered in between CH ₂ Cl ₂ (100 mL) and saturated sodium carbonate (20mL). The additional organic layer was separated and extracted the aqueous layer 50mL CH ₂ Cl _2. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a dark oil which was subjected to flash chromatography on silica using _2% MeOH / CH 2 Cl 2 then 5-10% 2M NH ₃ in MeOH / CH ₂ Cl ₂ gave a dark yellow residue. ¹ H-NMR (DMSO-d ₆ ) δ: 7.67 (d, J = 3.9 Hz, 1H), 7.55 (d, J = 3.9 Hz, 1H), 7.07 (dd, J = 3.9, 5.4 Hz, 1H), 6.57-6.48 (m, 3H), 6.23 (br s, 2H), 3.30-3.17 (m, 4H), 2.97-2.90 (m, 1H), 2.66 (t, J = 6.3 Hz, 2H), 2.21 (s) , 3H), 2.05-1.37 (m, 10H)

MS (ESI): 369.2 (M+1). ESI-HRMS calcd for C ₂₁ H ₂₉ N ₄ S ₁ (MH ⁺ ): 369.2107, observed: 369.2126.

Example 15

6-nitro-1-(2-oxopropyl)-3,4-dihydroquinolin-2(1H)-one

A suspension of 6-nitro-3,4-dihydroquinolin-2(1H)-one (950 mg, 4.94 mmol) and potassium carbonate (4.10 g, 29.64 mmol) in 12 mL of DMF with chloroacetone (787 μL, 9.89 mmol) was treated and stirred at room temperature overnight. The mixture was then cooled to 0 ° C and treated with 50 mL H ₂ O with stirring. After forming a precipitate, and filtered, washed with 50mL H ₂ O. The solid was collected and dried under reduced pressure overnight (1.01 g, 82.1%). ¹ H-NMR (DMSO-d ₆ ) δ: 8.17 (d, J = 2.4 Hz, 1H), 8.05 (dd, J = 2.4, 8.7 Hz, 1H), 7.05 (d, J = 8.7 Hz, 1H), 3.33 (s, 2H), 3.05 (t, J = 7.8 Hz, 2H), 2.66 (t, J = 7.8 Hz, 2H), 2.24 (s, 3H). MS (EI): 248 (M+)

6-nitro-1-(2-(pyrrolidin-1-yl)propyl)-3,4-dihydroquinolin-2(1H)-one

6-Nitro-1-(2-oxopropyl)-3,4-dihydroquinolin-2(1H)-one (500 mg, 2.01 mmol) and pyrrolidine (333 μL, 4.03 mmol) in 10 mL A solution of 1,2-dichloroethane (DCE) was treated with acetic acid (228 [mu]L, 4.03 <RTIgt; The suspension was stirred at room temperature overnight and then quenched with 10 mL 1N NaOH. This mixture was diluted to 15mL H ₂ O, then extracted with 2 × 100mL CH ₂ Cl _2. The combined to the organic portion flushed 50mL H ₂ O, dried over magnesium sulfate, filtered and concentrated to give a yellow residue, which was subjected to flash chromatography on silica, using 5% 2M NH ₃ in MeOH / CH ₂ Cl _2. A yellow oil (595 mg, 97.5%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 8.13 (dd, J = 2.7, 9.0 Hz, 1H), 8.07 (d, J = 2.7 Hz, 1H), 7.21. (d, J = 9.0 Hz, 1H), 4.21. Dd, J = 8.7, 14.1 Hz, 1H), 4.02 (dd, J = 5.4, 14.4 Hz, 1H), 3.00 (t, J = 7.2 Hz, 2H), 2.91-2.62 (m, 7H), 1.92-1.90 (m, 4H), 1.00 (d, J = 6.3 Hz, 3H). MS (ESI): 304.2 (M+1, 100%).

6-Amino-1-(2-(pyrrolidin-1-yl)propyl)-3,4-dihydroquinolin-2(1H)-one

6-Nitro-1-(2-(pyrrolidin-1-yl)propyl)-3,4-dihydroquinolin-2(1H)-one (585 mg, 1.93 mmol) and palladium on activated carbon A suspension of (10%, 103 mg, 0.096 mmol) in 15 mL of ethanol was stirred overnight in a hydrogen atmosphere. The suspension was filtered through a pad of silica gel. The filter pad to 20mL of 2M NH ₃ in methanol and the filtrate was concentrated to give a viscous oil flush. This crude product was used without further purification. (490 mg, 92.9%). ¹ H-NMR (CDCl ₃ ) δ: 7.20 (d, J = 8.7 Hz, 1H), 6.63 (dd, J = 2.4, 8.7 Hz, 1H), 6.51 (d, J = 2.4 Hz, 1H), 4.37 ( d, J = 7.2 Hz, 2H), 3.58 (brs, 2H), 2.82 - 2.77 (m, 2H), 2.63 - 2.58 (m, 2H), 2.1 (br s, 4H), 1.80-1.62 (br s, 5H), 1.30 (d, J = 6.6 Hz, 3H).

MS (ESI): 274.2 (M+1, 100%).

N-(2-Sideoxy-1-(2-(pyrrolidin-1-yl)propyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboxyindole Amine

a solution of 6-amino-1-(2-(pyrrolidin-1-yl)propyl)-3,4-dihydroquinolin-2(1H)-one (240 mg, 0.88 mmol) in 10 mL of EtOH. Treated with methylthiophene-2-carboquinone thiocarboxylate hydrogen iodide (501 mg, 1.76 mmol) and stirred at room temperature overnight. The mixture was diluted in CH ₂ Cl ₂ (10mL), and the Argon was bubbled through the solution for 20 min. The solution in CH ₂ Cl ₂ (100mL) and saturated sodium carbonate (20mL) between the layers. The additional organic layer was separated and extracted the aqueous layer 50mL CH ₂ Cl _2. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a yellow was applied to flash chromatography on silica using _2% MeOH / CH 2 Cl 2 then 5-10% 2M NH ₃ in MeOH / CH ₂ Cl ₂ . A yellow solid (200 mg, 59.4%) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 7.71 (d, J = 3.6 Hz, 1H), 7.57 (d, J = 5.4 Hz, 1H), 7.08-7.06 (m, 2H), 6.72-6.71 (m) , 2H), 6.41 (br s, 2H), 4.05 (dd, J = 9.0, 13.8 Hz, 1H), 3.83 (dd, J = 4.8, 13.8 Hz, 1H), 2.79-2.75 (m, 3H), 2.54 - 2.47 (m, 6H), 1.63 (br, 4H), 0.87 (d, J = 6.3 Hz, 3H).

MS (ESI): 383.2 (M+1). ESI-HRMS calculated for C ₂₁ H ₂₇ N ₄ SO (MH ⁺ ): 333.1900, observed: 355.1896.

Example 16:

1-(2-(pyrrolidin-1-yl)propyl)-1,2,3,4-tetrahydroquinolin-6-amine

A solution of 6-amino-1-(2-(pyrrolidin-1-yl)propyl)-3,4-dihydroquinolin-2(1H)-one (245 mg, 0.90 mmol) in 10 mL anhydrous THF It was cooled to 0 ℃, and by dropwise addition of 1M LiAlH ₄ (2.7mL, 2.7mmol) process in THF. The suspension was stirred at room temperature overnight. The mixture was then cooled to 0 ° C and treated with 1.5 mL of 1N NaOH dropwise with stirring. After stirring for 30 minutes, the suspension was diluted with 10mL CH ₂ Cl _2, Na ₂ SO ₄ to process. The suspension was filtered, and the solid was 20mL 5% 2M NH ₃ in MeOH / CH ₂ Cl ₂ rinse. The filtrate was concentrated and the dark residue was applied to flash chromatography on silica, using 5% 2M NH ₃ in MeOH / CH ₂ Cl ₂ to give a dark viscous oil (136mg, 58.4%). ¹ H-NMR (CDCl ₃ ) δ: 6.84 (br, 2H), 6.41 (br, 1H), 3.48 (dd, J = 4.2, 14.4 Hz, 1H), 3.24 - 3.19 (m, 4H), 3.91 (dd , J = 14.4, 4.2 Hz, 1H), 2.69-2.67 (m, 6H), 1.95-1.79 (m, 7H), 1.14 (d, J = 6.6 Hz, 3H).

MS (ESI): 260.2 (m+1).

N-(1-(2-(pyrrolidin-1-yl)propyl)-1,2,3,4-tetrahydroquinolin-6-yl) Thiophene-2-carboxyindole

A solution of 1-(2-(pyrrolidin-1-yl)propyl)-1,2,3,4-tetrahydroquinolin-6-amine (130 mg, 0.50 mmol) in 10 mL of EtOAc 2-Carbium imine thiocarboxylate hydrogen iodide (285 mg, 1.00 mmol) was treated and stirred at room temperature for 3 days. Argon was bubbled through the solution for 20 minutes. This solution was partitioned between CH ₂ Cl ₂ (100 mL) and sat. sodium carbonate (15 mL). The additional organic layer was separated and extracted the aqueous layer 50mL CH ₂ Cl _2. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a yellow residue which was subjected to flash chromatography on silica using _{2.5% MeOH / CH 2 Cl 2} , then 5-10% 2M NH ₃ in MeOH / CH ₂ Cl ₂ . A pale orange solid (100 mg, 54.3%) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 7.67 (d, J = 3.6 Hz, 1H), 7.55 (d, J = 4.2 Hz, 1H), 7.08-7.05 (m, 1H), 6.56-6.48 (m) , 3H), 6.25 (br s, 2H), 3.44 (dd, J = 4.5, 14.4 Hz, 1H), 3.33 - 3.25 (m, 2H), 2.95 (dd, J = 8.7, 13.8 Hz, 1H), 2.72 - 2.58 (m, 7H), 1.86-1.82 (m, 2H), 1.67 (br, 4H), 1.03 (d, J = 6.3 Hz, 3H).

MS (ESI): 369.2 (M+1). ESI-HRMS calcd for C ₂₁ H ₂₉ N ₄ S (MH ⁺ ): 369.2107, observed: 369.2113.

Example 17

1-methyl-N-phenylpiperidin-4-amine:

Aniline (2.0 g, 1.95 mL, 21.475 mmol), N-methyl-4-piperidone (2.64 mL, 21.475 mmol) and AcOH (1.21 mL, 21.475 mmol) in anhydrous 1,2-dichloroethane ( A solution of 20 mL) was treated with NaBH(OAc) ₃ (6.82 g, 32.21. The reaction was brought to room temperature and stirred overnight (16 h). The reaction solution was extracted into 1N NaOH _{CH 2 Cl 2 (2 × 25mL} ) (40mL) and basified and the product. The combined CH ₂ Cl ₂ layer was washed with brine (15mL) and dried (Na ₂ SO _4). The solvent was evaporated and the crude product was purified by column chromatography to (2M NH ₃ in _{MeOH: CH 2 Cl 2, 5} : 95) to give compound 1-methyl-piperidin slightly -N- phenyl-4-amine (4.0 g, 98%) solid. ¹ H NMR (DMSO- d ₆ ) δ: 1.29-1.42 (m, 2H), 1.82-1.88 (m, 2H), 1.93-2.02 (m, 2H), 2.15 (s, 3H), 2.68-2.74 (m) , 2H), 3.08-3.18 (m, 1H), 5.36 (d, 1H, J = 8.1 Hz), 6.47 (t, 1H, J = 7.2 Hz), 6.54 (d, 2H, J = 7.8 Hz), 7.03 (t, 2H, J = 7.2 Hz); ESI-MS (m/z, %) 191 (MH ⁺ , 100).

2-bromo-N-(1-methylpiperidin-4-yl)-N-phenylpropanamide

Compound -N- phenyl-1-methyl-piperidin-4-amine (1.0g, 5.255mmol) was in dry CH ₂ Cl ₂ (10mL), the in Et ₃ N (2.19mL, 15.766mmol) process, then Treated with 2-bromopropanyl bromide (0.61 mL, 5.780 mmol) at 0 ° C and stirred at rt for 1 h. The reaction was diluted with water (25mL) and the product was extracted into _{CH 2 Cl 2 (2 × 25mL} ). The combined of CH ₂ Cl ₂ layer was washed with brine (20mL) and dried (Na ₂ SO _4). The solvent was evaporated and the crude product was purified by column chromatography _{(MeOH: CH 2 Cl 2,} 5: 95) in order to obtain a compound 2-bromo -N- (1- methyl-piperidin-4-yl) -N- benzene Propionamide (1.5 g, 88%) solid. ¹ H NMR (DMSO- d ₆ ) δ: 1.09-1.33 (m, 2H), 1.59 (d, 3H, J = 6.3 Hz), 1.66-1.74 (m, 2H), 1.89-1.98 (m, 2H), 2.09 (s, 3H), 2.68-2.74 (m, 2H), 4.01 (q, 1H), 4.28-4.36 (m, 1H), 7.26-7.30 (m, 2H), 7.46-7.50 (m, 3H); ESI-MS (m/z, %) 327 and 325 (MH ⁺ , 100%).

3-methyl-1-(1-methylpiperidin-4-yl)porphyrin-2-one

3-methyl-1- (1-methyl-pyrrolidin-4-yl) indolin-2- one (0.31g, 0.953mmol) anhydrous AlCl ₃ (0.5g), and the resulting mixture of the resulting Stirred at 185 ° C for 2.5 h. The reaction was taken to EtOAc EtOAc (EtOAc)EtOAc. The combined ethyl acetate layer was washed with brine (15mL) and dried (Na ₂ SO _4). The solvent was evaporated and the crude product was purified by column chromatography _{(MeOH: CH 2 Cl 2,} 5: 95) to give 3- to-1- (1-methyl-piperidin-4-yl) indoline - 2-ketone (0.19 g, 82%) solid. ¹ H NMR (DMSO- d ₆ ) δ: 1.31 (d, 3H, J = 7.5 Hz), 1.50-1.58 (m, 2H), 1.99 (t, 2H, J = 11.7 Hz), 2.20 (s, 3H) , 2.32-2.42 (m, 2H), 2.84-2.90 (m, 2H), 3.44 (q, 1H), 3.99-4.10 (m, 1H), 7.00 (t, 1H, J = 7.2 Hz), 7.12 (d) , 1H, J = 7.8 Hz), 7.23 (t, 1H, J = 7.8 Hz), 7.30 (d, 1H, J = 7.5 Hz); ESI-MS (m/z, %) 245 (MH ⁺ , 100) .

3-methyl-1-(1-methylpiperidin-4-yl)-5-nitroindol-2-one

The compound 2-bromo--N- (1- methyl-piperidin-4-yl) -N- phenyl-propan-acyl amine (0.18g, 0.736mmol) in concentrated H ₂ SO ₄ (2mL) of a solution, fuming HNO ₃ (0.034 mL, 0.736 mmol) was taken from -5 to -10 ° C (ice + salt) and the resulting mixture was stirred at this temperature for 30 min. The reaction was quenched by adding crushed ice and then basified with 1N NaOH, and the product was extracted into _{CH 2 Cl 2 (2 × 20mL} ). The combined CH ₂ Cl ₂ layer was washed with brine (10 mL) and dried (Na ₂ SO _4). The solvent was evaporated and the crude product was purified by column chromatography to (2M NH ₃ in _{MeOH: CH 2 Cl 2, 2.5} : 97.5) to give compound 3-methyl-1- (1-methyl-piperidin-4-yl -5-Nitroporphyrin-2-one (0.13 g, 61%) solid. ¹ H NMR (DMSO- d ₆ ) δ: 1.39 (d, 3H, J = 7.5 Hz), 1.55-1.62 (m, 2H), 2.01 (t, 2H, J = 11.4 Hz), 2.20 (s, 3H) , 2.31-2.39 (m, 2H), 2.87 (d, 2H, J = 11.4 Hz), 3.63 (q, 1H), 4.06-4.16 (m, 1H), 7.39 (d, 1H, J = 9.3 Hz), 8.18-8.22 (m, 2H); ESI-MS (m/z, %) 290 (MH ⁺ , 100).

5-amino-3-methyl-1-(1-methylpiperidin-4-yl)porphyrin-2-one

a solution of the compound 3-methyl-1-(1-methylpiperidin-4-yl)-5-nitroindolino-2-one (0.1 g, 0.345 mmol) in anhydrous methanol (3 mL) Treatment with Ra-Ni (~0.05 g wet slurry) followed by hydrazine hydrate (0.1 mL, 3.456 mmol) at room temperature. The resulting mixture was refluxed for 2 minutes in a preheated oil bath and brought to room temperature. The reaction was filtered through a pad of Celite and washed with methanol (3×10 mL). The combined methanol layer was evaporated and the crude product was purified by column chromatography to (2M NH ₃ in _{MeOH: CH 2 Cl 2, 5} : 95) to obtain a compound 5-amino-3-methyl-1- (1 Methylpiperidin-4-yl)porphyrin-2-one (0.085 g, 96%). ¹ H NMR (DMSO- d ₆ ) δ: 1.24 (d, 3H, J = 7.8 Hz), 1.42-1.54 (m, 2H), 1.96 (t, 2H, J = 10.2 Hz), 2.18 (s, 3H) , 2.26-2.34 (m, 2H), 2.85 (d, 2H, J = 11.1 Hz), 3.25-3.30 (m, 1H), 3.91-4.02 (m, 1H), 4.75 (s, 2H), 6.43 (dd , 1H, J = 2.1, 8.4 Hz), 6.56 (d, 1H, J = 1.5 Hz), 6.79 (d, 1H, J = 8.4 Hz); ESI-MS (m/z, %) 260 (MH ⁺ , 100).

N-(3-Methyl-1-(1-methylpiperidin-4-yl)-2-oxooxalin-5-yl)thiophene-2-carboxyindoleimine

A solution of 5-amino-3-methyl-1-(1-methylpiperidin-4-yl)porphyrin-2-one (0.075 g, 0.289 mmol) in dry ethanol (3 mL) Treated with 6 (0.16 g, 0.578 mmol). The reaction was diluted with saturated NaHCO ₃ solution (20mL) and the product was extracted into _{CH 2 Cl 2 (2 × 15mL} ). The combined CH ₂ Cl ₂ layer was washed with brine (10 mL) and dried (Na ₂ SO _4). The solvent was evaporated and the crude product was purified by column chromatography to (2M NH ₃ in _{MeOH: CH 2 Cl 2, 5} : 95) to give compound 17 (0.095g, 90%) solid. ¹ H NMR (DMSO- d ₆ ) δ; 1.32 (d, 3H, J = 7.8 Hz), 1.50-1.60 (m, 2H), 2.00 (t, 2H, J = 11.4 Hz), 2.20 (s, 3H) , 2.31-2.42 (m, 2H), 2.88 (d, 2H, J = 11.1 Hz), 3.36 (q, 1H), 4.01-4.10 (m, 1H), 6.41 (brs, 2H), 6.73 (d, 1H) , J = 8.1 Hz), 6.85 (s, 1H), 7.05-7.10 (m, 2H), 7.59 (d, 1H, J = 5.1 Hz), 7.71 (d, 1H, J = 3.3 Hz); ESI-MS (m/z, %) 369 (MH ⁺ , 40), 272 (67%), 185 (100), 176 (30); ESI-HRMS calculated for C ₂₀ H ₂₅ N ₄ OS (MH ⁺ ), Calculated value: 369.1743; observed value: 369.1759.

Example 18

1-(1-methylpiperidin-4-yl)-1,2,3,4-tetrahydroquinoline

A solution of 1,2,3,4-tetrahydroquinoline (1.0 mL, 7.94 mmol) in 20 mL of 1,2-dichloroethane as 1-methylpiperidin-4-one (2.76 mL, 23.8 mmol The treatment was treated with sodium triethoxysulfonium borohydride (8.4 g, 39.7 mmol) and thenEtOAc (2. The suspension was stirred at room temperature for 1 day. The mixture was then cooled to 0 ° C, quenched with 5 mL 1N NaOH and stirred for 20 min. This suspension was extracted with 100 mL of CH ₂ Cl ₂ . The organic layer was dried over magnesium sulfate, filtered and concentrated to give a pale residue, which was subjected to flash chromatography on silica, using 5% MeOH / CH ₂ Cl ₂ followed by 5% 2M NH ₃ in MeOH / CH ₂ Cl ₂ . Obtained a yellow oil (440 mg, 24.1%) ¹ H-NMR (CDCl ₃ ) δ: 7.07-7.02 (m, 1H), 6.95 (d, J = 7.5 Hz, 1H), 6.65 (d, J = 8.4 Hz, 1H), 6.55 (pseudo t, J = 7.8 Hz, 1H), 3.65-3.55 (m, 1H), 3.20 (t, J = 5.7 Hz, 2H), 2.99-2.95 (m, 2H), 2.73 (t, J = 6.0 Hz, 2H), 2.31 (s, 3H), 2.11-2.05 (m, 2H), 1.93-1.73 (m, 6H).

MS (ESI): 231.2 (M+1, 100%).

6-bromo-1-(1-methylpiperidin-4-yl)-1,2,3,4-tetrahydroquinoline

A solution of 1-(1-methylpiperidin-4-yl)-1,2,3,4-tetrahydroquinoline (500 mg, 2.17 mmol) in 7 mL of DMF was cooled to 0 ° C then NBS (386 mg) , 2.17 mmol) was treated with 7 mL of DMF. The reaction was stirred for 2 hours at 0 ℃, then 30mL H ₂ O treatment. The suspension was extracted with 100 mL EtOAc. The organic layer was dried over magnesium sulfate, filtered and concentrated to give a dark residue using 5%, 2M NH ₃ was filtered through a short silica gel plug in _{MeOH / CH 2 Cl 2 (100mL} ). The filtrate was concentrated and subjected to flash chromatography on silica, using 5% MeOH / CH ₂ Cl ₂ followed by 5% 2M NH ₃ in MeOH / CH ₂ Cl _2. A pale yellow oil (490 mg, 73.0%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 7.10 (dd, J = 2.1, 10.8 Hz), 7.04-7.03 (m, 1H), 6.50 (d, J = 9.0 Hz, 1H), 3.57-3.47 (m, 1H) ), 3.18 (t, J = 5.7 Hz, 2H), 2.98-2.94 (m, 2H), 2.68 (t, J = 6.0 Hz, 2H), 2.31 (s, 3H), 2.10-2.02 (m, 2H) , 1.91-1.69 (m, 6H). MS (ESI): 309.1 and 311.1 (M+1, 100%).

1-(1-methylpiperidin-4-yl)-1,2,3,4-tetrahydroquinolin-6-amine

6-Bromo-1-(1-methylpiperidin-4-yl)-1,2,3,4-tetrahydroquinoline (425 mg, 1.37 mmol) and Pd ₂ (dba) ₃ (63 mg, 0.07 mmol) a solution of 10 mL of anhydrous THF, treated with lithium hexamethyldiazepine (2.8 mL of a 1 M solution in THF, 2.8 mmol), and then with P t Bu ₃ (830 μL of 10% wt in hexanes, 0.27 mmol) )deal with. The dark brown suspension obtained was heated at 100 ° C for 2 hours. The mixture was cooled to room temperature and treated with 7 mL of 1N HCl solution and then stirred at room temperature for 15 min. This mixture CH ₂ Cl ₂ (100mL) and between 1N NaOH (20mL) delamination. The organic layer was separated and the aqueous layer was extracted with more than ₂ times 100mL CH ₂ Cl 1. The combined organic portions were washed with brine, dried over sodium sulfate, dried &lt The residue was subjected to flash chromatography on silica, using _{5% MeOH / CH 2 Cl 2} . Then -10% 2M NH ₃ in MeOH / CH ₂ Cl ₂ to give a viscous dark brown residue (163mg, 48.5%). ¹ H-NMR (CDCl ₃ ) δ: 6.54 (d, J = 8.7 Hz, 1H), 6.49 (dd, J = 2.7, 8.7 Hz, 1H), 6.42-6.41 (m, 1H), 3.54-3.44 (m) , 1H), 3.20 (brs, 2H), 3.11 (t, J = 5.4 Hz, 2H), 2.97 - 2.93 (m, 2H), 2.66 (t, J = 6.0 Hz, 2H), 2.30 (s, 3H) , 2.08-2.01 (m, 2H), 1.91-1.71 (m, 6H).

MS (ESI): 246.2 (M+1, 100%).

N-(1-(1-methylpiperidin-4-yl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboxyindoleimide

a solution of 1-(1-methylpiperidin-4-yl)-1,2,3,4-tetrahydroquinolin-6-amine (150 mg, 0.61 mmol) in 10 mL of EtOH to methylthiophene-2 - Carbonium imine thiocarboxylate hydrogen iodide (349 mg, 1.22 mmol) was taken and stirred at room temperature overnight. This mixture was argon into the pump for 20 minutes then layered Room in CH ₂ Cl ₂ (100 mL) and saturated sodium carbonate (20mL). The aqueous layer was an additional 50mL CH ₂ Cl ₂ extracted with. The combined organic layers were dried over sodium sulfate and concentrated to give a dark oil which was subjected to flash chromatography on silica, using 5% MeOH / CH ₂ Cl ₂ then 5-10% 2M NH ₃ in MeOH / CH ₂ Cl ₂ to get 18 brown solids. ¹ H-NMR (DMSO-d ₆ ) δ: 7.67 (d, J = 3.6 Hz, 1H), 7.54 (d, J = 5.4 Hz, 1H), 7.06 (pseudo t, J = 4.2 Hz, 1H), 6.63 -6.48(m,3H), 6.21(br s,2H),3.54-3.47(m,1H),3.11(t,J=5.7Hz,2H),2.86-2.82(m,2H),2.63(t, J = 6.0 Hz, 2H), 2.17 (s, 3H), 2.03-1.96 (m, 2H), 1.84-1.57 (m, 6H).

MS (ESI): 355.2 (M+1, 100%). ESI-HRMS calculated for C ₂₀ H ₂₆ N ₄ S (MH ⁺ ): 355.1950, observed: 355.1938

Example 19a: nNOS (human), eNOS (human) and iNOS (human) enzyme assays

Recombinant human inducible NOS (iNOS) can be produced by baculovirus-infected Sf9 cells (ALEXIS). In the radiometric method, NO synthase activity was determined by measuring the conversion of [ ³ H]L-arginine to [ ³ H]L-citrulline. To measure iNOS, enzymes added to 10 μ L to 100 μ L of 100mM HEPES, pH = 7,4, containing 1mM CaCl _2, 1mM EDTA, 1mM dithiothreitol, 1 μ M FMN, 1 μ M FAD, 10 μ M tetrahydrobiopterin, 120 μ M NADPH, and 100nM CaM.

To measure enzyme inhibition, a 15 μ L of test substance solution is added to the enzyme assay solution, followed by pre-incubation at room temperature for 15 minutes. The reaction by addition of 20 μ L L- arginine containing 0.25 μ Ci f ^[3 H] arginine / mL and 24 μ M L- arginine start. The total volume of the reaction mixture was 150 μL per well. The reaction was carried out at 37 ° C for 45 minutes. The reaction by addition of 20 μ L of ice - cold buffer containing 100mM HEPES, 3mM EGTA, 3mM EDTA , pH = 5.5 stopped. [ ³ H]L-citrulline was separated by DOWEX (ion exchange resin DOWEX 50W X 8-400, SIGMA), and the DOWEX was separated by centrifugation at 12,000 g for 10 minutes. 70 μ L of the supernatant was added to an amount of 100 μ L of scintillation fluid, and a liquid scintillation counter to calculate the sample (1450 Microbeta Jet, Wallac). The difference between the activity recovered from the test solution and the observed value of the control group sample containing the 240 mM inhibitor L-NMMA was reported as the NOS activity. All analyses were performed at least two replicates. The standard deviation is less than 10%. These results show the selectivity of the compounds of the invention for inhibition of nNOS. The results of the exemplified compounds of the present invention are shown in Tables 3 and 4.

Human nNOS and eNOS experimental plans: Reagents and materials

Enzyme: nitric oxide synthase (neuron, human recombinant) nNOS I, Cat. No. ALX-201-068, Axxora LLC, CA 92121, USA nitric oxide synthase (endothelial, human recombinant) eNOS III, Cat.No.ALX-201-070, Axxora LLC

L-NMMA N ^G -monomethyl -L-arginine 1/04/05,Cat # A17933,Batch # 04-11-9002,Novabiochem

L-NAME N ^G -nitro-L-arginine methyl ester Cat # N5751, Aldrich

2X reaction. Buffer: 50 mM Tris-HCl (pH 7.4), Cat. No. 93313, Sigma-Aldrich Co.

6μM tetrahydrobiopterin (BH ₄ ), Cat.No.T4425, Sigma

2 μM flavin adenine dinucleotide (FAD), Cat. No. F6625, Sigma

2μM flavin adenine mononucleotide (FMN), Cat.No.F8399, Sigma

Stop buffer: 50 mM N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid

(HEPES) (pH 5.5), H7523, Sigma and 5 mM ethylenediamine Tetraacetic acid (EDTA), Cat.No.EDS, Sigma

NADPH: 10 mM freshly prepared on the day of the test, Cat. No. N7505, Sigma

Calcium Chloride: 6mM, Cat.No.21107, Sigma

Calcitonin : 1 mM, Cat. No. P2277, Sigma

[ ³ H]-L-arginine: 1 μ Ci/reaction, 40-70 Ci/mmol, Cat. No. TRK-698, Amersham Biosciences

L-arginine: 2.5 μ M (final analytical concentration), Cat. No. A5131, Sigma

Balanced Resin: AG-50W X8 Resin in HEPES Buffer (pH 5.5), Cat. No.1421441, Bio-Rad Laboratories Ltd.

Rotating Cup & Stand: Cat.No.C8163, Fisher Scientific

Liquid scintillation counter: Tri-Carb 2000CA/LL, Canberra Packard Canada.

Liquid scintillation fluid: Cat. No. 6012239, Ultima Gold, Perkin-Elmer Life and Analytical Sciences, MA

CO ₂ incubator: Lab-Line Enviro Shaker.

Microcentrifuge : Mikro 20.

Vortex Mixer: Mini Vortex Mixer, IKA

Human nNOS and eNOS procedures

From 2 to 5 mg of powder, the original base solution of the test compound was prepared at a concentration of 6 mM. The original base solution of each test compound was freshly prepared in distilled water on the day of the experiment to give a final concentration of 6 mM. To determine the IC ₅₀ values, in 3-fold serial dilutions, the concentration of test compound 12 was prepared. For nNOS range of test compound concentrations of 0.001 to 300 μ M, for eNOS who 0.003 - 1000 μ M. A carrier or inhibitor of the test compound is used as a blank control group. For non-specific activity, 100 μM L-NMMA was used. The IC ₅₀ concentration of L-NAME was paralleled as a control group.

program

All cultures were performed in two replicates.

The following ingredients so as to trace dropper was added to a polypropylene microcentrifuge tube, the reaction mixture was prepared on ice: 10 μ L of the test compound solution, inhibitor or control group (vehicle or L-NMMA)

25 μ L reaction buffer {25mM Tris-HCl, 0.6μM BH4,0.2μM FMN, 0.2μM FAD}

5 μ L 10mM NADPH solution {1mM} (prepared fresh in 10mM Tris-HCl (pH 7.4)

_{5 μ L 6mM CaCl 2 {600μM} }

5 μ L 1mM calcium regulating hormone {100μM}

5 μ L 0.02 μ g / μ L nNOS or 0.12 μ g / μ L eNOS

The above reaction mixture was pre-incubated for 15 minutes at room temperature.

The reaction started by adding the substrate (in 5 μ L, containing 1 μ Ci ^[3 H] -L- arginine +2.5 μ M L- arginine without calibration) to the reaction mixture. The total reaction volume was 60 μL.

Mix, use a vortex mixer, and incubate the above reaction mixture for 30 minutes at 37 ° C in an incubator.

During the period at the end of incubation, 400 μ L of ice-cold stop buffer to stop the reaction. (Stop EDTA in buffer to sequester all available calcium)

Mix, use a vortex mixer, transfer the reaction sample to a rotating cup, centrifuge, and centrifuge at 13,000 rpm for 30 seconds at room temperature using a microcentrifuge.

Rotary cup is removed from the holder, and transfer 450 μ L eluate (containing the unbound L- citrulline) to the scintillation vial. 3 mL of scintillation fluid was added and the radioactivity was quantified in a liquid scintillation counter.

IC ₅₀ values _were calculated: data analysis using dose-S - Response (various slope) curve to determine the IC ₅₀ values of test compounds.

Y = bottom + (top-bottom) / (1 + 10 ˆ ((LogIC ₅₀ - X) * hill slope)) X is the logarithm of the concentration of the test compound or inhibitor

Y is the amount of L-citrulline formed (pmol)

The bottom represents the lowest Y value and the top represents the highest Y value. Same as "4 parameter logarithmic equation"

The slope factor (also known as the slope of the hill) describes the steepness of the curve. The standard competition binding curve according to the quality action rule has a slope of -1.0. If the slope is slow, the slope will therefore be a negative fraction, such as -0.85 or -0.60.

Example 19b: Analysis of nNOS (rat), eNOS (rat) and iNOS (mouse) enzymes

Recombinant rat or mouse NO synthetase (iNOS, eNOS, NNOS) was expressed in Sf9 cells (Sigma), 36 mg prot/ml (Bradford). The solution was in 50 mM Hepes, pH 7.4 with 10% glycerol.

Inhibition of NOS is determined by measuring the formation of L-[3H] citrulline from L-[3H] arginine. Enzyme Analysis Embodiment [3H] arginine / ml, 120 μ M NADPH, 1 μ M FAD and FMN, 10 μ M BH4,100nM CaM, 100mM Hepes the presence of _{0,25 μ Ci, 2,4mM CaCl 2,} 24 μ M L-arginine, 1 mM EDTA, 1 mM DTT. Stop buffer: 100 mM Hepes, pH 5.5, 3 mM EDTA, 3 mM EGTA.

Enzymes and inhibitors were pre-incubated for 35 minutes in the presence of NADPH prior to the start of the reaction by the addition of arginine. The incubation was continued for 45 minutes, after which time the reaction mixture was quenched and [3H] citrulline was isolated from the unreacted matrix in a 96 well format on a DOWEX 50W X 8-400 ion exchange resin. The results of the exemplified compounds of the present invention are also shown in Tables 3 and 4.

Rodent data is in brackets.

Example 20: Precursor valence of a neuropathic pain state pattern

The potency of the compound of the present invention for treating neuropathic pain is used in The assessment of the anti-hyperalgesic and anti-tactile activity precursors of standard animal models caused by various methods was performed. The details are as follows.

(a) Chung mode of injury-induced neuropathic pain: Chung spinal nerve connection SNL mode test The experimental design of neuropathic pain is shown in Figures 1 and 5. Nerve junction injury was performed according to the method described by Kim and Chung (Kim and Chung, Pain 50: 355-363, 1992). This technical step predicts neurological sensational sensation, including perceptual tenderness, thermal hyperalgesia, and control of the affected paw. Rats were anesthetized with haloethane and the spine of the L4 to S2 region was exposed. L5 and L6 spinal nerves were exposed, carefully separated, and firmly attached to the DRG end with a 4-0 suture. After confirming the stability of the condition in the body, the wound was sutured and the animals were returned to their respective cages. The rats in the camouflage operation were prepared in the same manner except that the L5/L6 spinal nerves were not connected. Any rat that showed loss of exercise was euthanized. After the recovery period following surgical intervention, the rats showed sensitivity to pain and normal non-painful stimuli.

IP injections of standard doses (3, 10, and 30 mg/kg) were performed according to published procedures, showing nNOS selective compounds 11 (see Figure 2), 23 (see Figure 4), 37 (Figure 9), 47 (Figure 10), 54 (Fig. 11), 28 (Fig. 12), the anti-hyperalgesic effect, or the anti-tender effect of compound 23 (Fig. 6). Compound 3 showed no antihyperalgesic effect (Fig. 3).

Example 21:

In another embodiment, the compounds of the invention are useful in the treatment of CNS disorders. Preferably, the compounds of the invention should be CNS permeable. Better one An example of the compound of the invention is Example 11, which is a compound which exceeds the poor permeability of the CNS, for example, Example 3.

Two different compounds were delivered to the Chung animal model of neuropathic pain (CNS dysregulation) at the same dose, even though the nNOS values were similar. Although other factors may be involved, activity is related to lipophilicity.

Example 11. nNOS = 0.253 μ M, eNOS = 37.7 μ M

Example 3. nNOS = 0.58 μ M, eNOS = 41.1 μ M

Example 22

N-(2-iodophenyl)-1-methylpiperidin-4-amine

A solution of 2-iodoaniline (1.0 g, 4.57 mmol) in 15 mL of 1,2-dichloroethane was treated with 1-methylpiperidin-4-one (530 μL, 4.57 mmol). Treatment with sodium borohydride (1.55 g, 7.31 mmol) followed by acetic acid (259 uL). The suspension was stirred at room temperature for 21 hours. The mixture was then cooled to 0.degree. C., quenched with 20 mL 1N NaOH and extracted with 2×100 mL CH ₂ Cl ₂ . The combined organic layers were dried with MgSO4, filtered and evaporated. The residue was subjected to flash chromatography on silica gel using 5% 2M NH ₃ in MeOH / CH ₂ Cl _2. A pale yellow oil (579 mg, 40.2%) was obtained. ¹ H-NMR (CDCl ₃ ) δ 7.64 (dd, J = 1.2, 8.1 Hz, 1H), 7.21-7.15 (m, 1H), 6.57 (d, J = 8.1 Hz, 1H), 6.44 - 6.39 (m, 1H), 4.12-4.10 (m, 1H), 3.37-3.35 (m, 1H), 3.79-2.75 (m, 2H), 2.31 (s, 3H), 2.22-2.03 (m, 4H), 1.65-1.53 ( m, 2H). MS (ESI): 317.1 (M+1, 100%)

(E)-Methyl 3-(2-(1-methylpiperidin-4-ylamino)phenyl)acrylate

N-(2-iodophenyl)-1-methylpiperidin-4-amine (550 mg, 1.74 mmol), methyl acrylate (157 μL, 1.74 mmol), palladium acetate (39 mg, 0.17 mmol), tri-o-toluene A solution of phosphine (106 mg, 0.35) and diisopropylethylamine (608 μL, 3.48 mmol) in 7 mL of DMF was deoxygenated with argon and then heated at 100 ° C for 5 hours. The mixture was cooled to room temperature, then in EtOAc (150mL) was partitioned between H ₂ O (20mL) and. After extraction, the organic layer was separated and rinsed with brine. The organic layer was dried over sodium sulfate, filtered and concentrated to give a yellow residue, which was subjected to flash chromatography on silica, using 5%, 2M NH ₃ in MeOH / CH ₂ Cl _2. A viscous yellow oil (350 mg, 73.4%) was obtained. ¹ H-NMR (CDCl ₃ ) δ 7.85 (d, J = 15.9 Hz, 1H), 7.37-7.35 (m, 1H), 7.24-7.21 (m, 1H), 6.72-6.67 (m, 2H), 6.33 ( d, J = 15.9 Hz, 1H), 3.88-3.85 (m, 1H), 3.81 (s, 3H), 3.36 (brs, 1H), 2.84-2.81 (m, 2H), 2.31 (s, 3H), 2.18 -2.05 (m, 4H), 1.63-1.51 (m, 2H). MS (ESI): 275.2 (M+1, 100%)

Methyl 3-(2-(1-methylpiperidin-4-ylamino)phenylpropionate

(E)-Methyl 3-(2-(1-methylpiperidin-4-ylamino)phenyl)acrylate (330 mg, 1.20 mmol) and palladium-carbon (10% wt, 128 mg, 0.12 mmol) ) A suspension of 20 mL of EtOAc was stirred in a hydrogen balloon overnight. The suspension was diluted with MeOH (50 mL) and filtered over EtOAc. The diatomaceous earth pad was rinsed with 10 mL of MeOH. The filtrate was concentrated and the residue was subjected to flash chromatography on silica gel using 5% 2M NH ₃ in MeOH / CH ₂ Cl _2. To give a pale yellow oil (300mg, 90.4%). ¹ H-NMR (CDCl ₃ ) δ 7.14-7.08 (m, 1H), 7.04-7.01 (m, 1H), 6.67-6.63 (m, 2H), 3.76-3.74 (m, 1H), 3.69 (s, 3H) ), 3.35 (brs, 1H), 2.82-2.77 (m, 4H), 2.65-2.60 (m, 2H), 2.31 (s, 3H), 2.19-2.06 (m, 4H), 1.61-1.49 (m, 2H) ). MS (ESI): 277.2 (M+1, 100%).

1-(1-methylpiperidin-4-yl)-3,4-dihydroquinolin-2(1H)-one

Methyl 3- (2- (1-methyl-piperidin-4-yl) phenyl propionate (1.1g, 3.98mmol) / 5mL H 2 O The solution was 20mL MeOH, in 1N NaOH (8.8 The mixture was treated with EtOAc (3 mL, EtOAc, EtOAc, EtOAc, EtOAc, EtOAc. the mixture was concentrated on a rotary evaporator, and washed with saturated Na ₂ CO ₃ was made basic. this solution was ₂ × 100mL CH 2 Cl 2 extraction. the combined organic portion over magnesium sulfate, filtered and concentrated to give a light brown residue, which was subjected to flash chromatography on silica, using 5%, 2M NH ₃ in MeOH / CH ₂ Cl _2. to give a pale yellow solid ^{(320mg, 78.2%). 1} H-NMR (CDCl 3) δ 7.24-7.16(m,3H), 7.02-6.97(m,1H),4.47-4.34(m,1H),2.99-2.95(m,2H),2.83-2.70(m,2H),2.68-2.55(m , 4H), 2.33 (s, 3H), 2.13-2.06 (m, 2H), 1.72-1.69 (m, 2H). MS (ESI): 245.2 (M+1, 100%).

1-(1-methylpiperidin-4-yl)-6-nitro-3,4-dihydroquinolin-2(1H)-one

1- (1-methyl-pyrrolidin-4-yl) -3,4-dihydro-quinolin -2 (1H) - one (305mg, 1.25mmol) in a solution of concentrated H ₂ SO ₄ (4mL) of the order The fuming HNO ₃ (53 μL, 1.25 mmol) was treated at -5 to -10 ° C (ice / MeOH), and the obtained mixture was stirred at the same temperature for 30 minutes. The reaction was quenched by the addition of crushed ice and basified with 1N NaOH and the product was extracted to CH ₂ Cl ₂ (2×50 mL). The combined CH ₂ Cl ₂ layer was dried (Na ₂ SO _4), filtered, and the solvent was evaporated. The crude material was taken from EtOAc (EtOAc) ¹ H-NMR (CDCl ₃ ) δ 8.10-8.05 (m, 2H), 7.33 (d, J = 8.7 Hz, 1H), 4.50 - 4.39 (m, 1H), 3.01-2.90 (m, 4H), 2.67- 2.54 (m, 4H), 2.33 (s, 3H), 2.15-2.08 (m, 2H), 1.74-1.70 (m, 2H). MS (ESI): 290.2 (M+1, 100%).

6-Amino-1-(1-methylpiperidin-4-yl)-3,4-dihydroquinolin-2(1H)-one

1-(1-Methylpiperidin-4-yl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (300 mg, 1.04 mmol) and palladium on activated carbon (10) A suspension of % wt, 55 mg, 0.05 mmol) in 20 mL ethanol / 4 mL THF was stirred overnight in a hydrogen balloon. This suspension was filtered through a pad of celite. The filter pad was rinsed with 50 mL of methanol, and the filtrate was concentrated to give a viscous oil. This crude product was used without further purification. (250 mg, 92.6%). ¹ H-NMR (CDCl ₃ ) δ 7.06 (d, J = 9.3 Hz, 1H), 6.54 - 6.49 (m, 2H), 4.46 - 4.36 (m, 1H), 3.42 (brs, 2H), 2.97 - 2.94 ( m, 2H), 2.73-2.49 (m, 6H), 2.31 (s, 3H), 2.27-2.05 (m, 2H), 1.27-1.21 (m, 2H). MS (ESI): 260.2 (M+1, 100%).

N-(1-(1-methylpiperidin-4-yl)-2-oxooxy-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboxyindoleimine amine

A solution of 6-amino-1-(1-methylpyrrolidin-4-yl)-3,4-dihydroquinolin-2(1H)-one (240 mg, 0.93 mmol) in 15 mL of EtOH The thiophene-2-carbonium imine thiocarboxylate hydrogen iodide (528 mg, 1.85 mmol) was treated and stirred at room temperature overnight. TLC analysis indicated that the starting material (amine) was still present. Additional equivalents of methylthiophene-2-carboquinone thiocarboxylate hydrogen iodide (265 mg, 0.93 mmol) were added and stirring was continued overnight at room temperature. TLC analysis indicated that the starting material (amine) was still present. The reaction mixture was take into argon for 20 minutes to promote far; then partitioned between CH ₂ Cl ₂ at (100 mL) and saturated sodium carbonate (20mL). The aqueous layer was _extracted with additional 50mLCH ₂ Cl. The combined organic layers were dried over sodium sulfate and concentrated to give a yellow oil which was subjected to flash chromatography on silica, using _{5% MeOH / CH 2 Cl 2} , then 5-10% 2M NH ₃ in MeOH / CH ₂ Cl ₂ gave a yellow semi-solid. Analysis by ¹ H-NMR, this mixture contains the starting amine and the desired product. This mixture was dissolved in MeOH (10 mL), EtOAc (EtOAc m. The reaction was taken up and purified EtOAcqqqqqq ¹ H-NMR (DMSO-d ₆ ) δ 7.73 (d, J = 2.3 Hz, 1H), 7.59 (d, J = 4.8 Hz, 1H), 7.16-7.15 (m, 1H), 7.09 (dd, J = 5.1, 6.3 Hz, 1H), 6.74-6.70 (m, 2H), 6.44 (brs, 2H), 4.05-3.97 (m, 1H), 2.86-2.50 (m, 8H), 2.18 (s, 3H), 2.00 -1.93 (m, 2H), 1.59-1.55 (m, 2H). MS (ESI): 369.2 (M+1, 100%). ESI-HRMS calculated for C ₂₀ H ₂₅ N ₄ SO (MH ⁺ ): 369.1739, observed: 369.1743

Examples 23 and 24

N-(1-(2-(1-methylpyrrolidin-2-yl)ethyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboxyindoleimine Amine (Example 14)

The title compound was prepared as described in Example 14.

Separation of (+)-isomers and ( -)-isomers : separation of the mirror image isomers was achieved by chiral HPLC.

Column: Chiracel AD-H 20 x 250mm

(-)-isomer (23) : 1 ^st elutes the isomer. The free base is converted to the dihydrogen chloride salt by standard methods. Optical rotation: ²⁵ [α] ₅₈₉ = -0.18 °, c = 0.5 MeOH. ¹ H-NMR (CD ₃ OD) δ 8.02-7.99 (m, 2H), 7.34 (pseudo t, J = 4.5 Hz, 1H) , 7.11-7.03 (m, 2H), 6.85 (d, J = 8.4 Hz, 1H), 3.70-3.65 (m, 1H), 3.51-3.37 (m, 4H), 3.20-3.11 (m, 2H), 2.93 (s, 3H), 2.84-2.80 (m, 2H), 2.50-1.75 (m, 8H). MS (ESI): 369.2 (M+1). ESI-HRMS calcd for C ₂₁ H ₂₉ N ₄ S (MH ⁺ ): 369.2107, observed: 369.2118.

(+)-isomer (24) : 2 ^nd elution isomer. The free base is converted to the dihydrogen chloride salt by standard methods. Optical rotation: ²⁵ [α] ₅₈₉ = +0.17°, c = 0.48 in MeOH. ¹ H-NMR (CD ₃ OD) δ 8.03-7.99 (m, 2H), 7.34 (pseudo t, J = 4.5 Hz, 1H) , 7.12-7.03 (m, 2H), 6.85 (d, J = 8.7 Hz, 1H), 3.73-3.65 (m, 1H), 3.51-3.39 (m, 4H), 3.20-3.11 (m, 2H), 2.93 (s, 3H), 2.84-2.80 (m, 2H), 2.50-1.75 (m, 8H). MS (ESI): 369.2 (M+1). ESI-HRMS calcd for C ₂₁ H ₂₉ N ₄ S (MH ⁺ ): 369.2107, observed: 369.2113.

Example 25

4,5-dihydro-1H-benzo[b]azepine-2(3H)-one

3,4-dihydro-naphthalene -1 (2H) - one of the suspension mixture (2.0g, 13.68mmol) and sodium azide (1.11g, 17.10mmol) in 14mL CHCl ₃ and of 3mL H ₂ O, in It was heated at 40 ° C and then treated dropwise with H ₂ SO ₄ for 20 minutes. This mixture was diluted with 50 mL of H ₂ O and filtered. The solid was _hot, H ₂ O slurry was cooled and filtered to give a gray solid (1.45g, 65.6%). ¹ H-NMR (DMSO-d ₆ ) δ 9.49 (s, 1H), 7.25-7.22 (m, 2H), 7.19-7.21 (m, 1H), 6.95 (d, J = 7.8 Hz, 1H), 2.70- 2.65 (m, 2H), 2.15-2.07 (m, 4H). MS (EI): 161 (M+).

7-nitro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one

-1H- 4,5-dihydro-benzo [b] Boom nitrogen -2 (3H) - one (1.42g, 8.81mmol) in concentrated H ₂ SO ₄ (25mL) of solution of fuming HNO ₃ (414μL , 8.81 mmol) was treated at -5 to -10 ° C (ice / MeOH). The resulting solution was stirred at the same temperature for 30 minutes. The reaction was quenched by adding crushed ice. The resulting suspension was diluted with water (50 mL) and filtered. The solid was washed with 4 x 50mL H ₂ O, collected and dried overnight under reduced pressure. Yield: 1.0 g, 55.1%. ¹ H-NMR (DMSO-d ₆ ) δ 10.08 (s, 1H), 8.19 (d, J = 2.4 Hz, 1H), 8.11 (dd, J = 2.4, 8.7 Hz, 1H) ), 7.15 (d, J = 8.7 Hz, 1H), 2.83 - 2.79 (m, 2H), 2.26 - 2.13 (m, 4H). MS (EI): 206 (M+).

1-(2-(Dimethylamino)ethyl)-7-nitro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one

7-Nitro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one (490 mg, 2.38 mmol), 2-chloro-N,N-dimethylethylamine hydrogen chloride A suspension of (685 mg, 4.75 mmol) and potassium carbonate (1.97 g, 14.28 mmol) in 15 mL of DMF was stirred at room temperature for 1 day. TLC analysis showed that the starting material was still present. This mixture was treated with 2-chloro-N,N-dimethylethylamine hydrogen chloride (685 mg, 4.75 mmol) and potassium carbonate (1.97 g, 14.28 mmol). After the mixture was poured into 50mL H ₂ O, and then extracted with 2 × 100mL EtOAc. The combined organic portions were washed with brine, dried over sodium sulfate, filtered and evaporated The residue was subjected to flash chromatography on silica using 2-5% 2M NH ₃ in MeOH / CH ₂ Cl ₂ to give a yellow viscous oil (412mg, 62.4%). ¹ H-NMR (DMSO-d ₆ ) δ 8.21 - 8.15 (m, 2H), 7.67 (d, J = 8.7 Hz, 1H), 3.92-3.90 (m, 2H), 2.87-2.83 (m, 2H), 2.27 (t, J = 6.3 Hz, 2H), 2.21-2.11 (m, 4H), 2.03 (s, 6H). MS (ESI): 278.1 (M+1).

7-Amino-1-(2-(dimethylamino)ethyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one

1-(2-(Dimethylamino)ethyl)-7-nitro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one (400 mg, 1.44 mmol) And a suspension of palladium on activated carbon (10% wt, 153 mg, 0.14 mmol) in 20 mL of ethanol was stirred overnight in a hydrogen atmosphere. This suspension was filtered through a pad of celite. The filter pad was rinsed with 50 mL of methanol and the filtrate was concentrated to give a pale white solid (350 mg, 98.3%). ¹ H-NMR (CDCl ₃ ) δ 6.99 (d, J = 8.4 Hz, 1H), 6.58 (dd, J = 2.4, 8.4 Hz, 1H), 6.50 (d, J = 2.4 Hz, 1H), 3.73 - 3.65 (m, 2H), 3.69 (brs, 2H), 2.72-2.55 (m, 2H), 2.39 (t, J = 6.9 Hz, 2H), 2.21-2.11 (m, 4H), 2.19 (s, 6H). MS (ESI): 248.2 (M+1).

N-(1-(2-(dimethylamino)ethyl)-2-yloxy-2,3,4,5-tetrahydro-1H-benzo[b]azepine-7-yl) Thiophene-2-carboxyindole

7-Amino-1-(2-(dimethylamino)ethyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one (100 mg, 0.40 mmol) The solution was treated with methyl thiophene-2-carboquinone thiocarboxylate hydrogen iodide (231 mg, 0.81 mmol) in 10 mL of EtOH and stirred at room temperature overnight. CH ₂ Cl ₂ (20mL) was diluted to promote, and the mixture was bubbled with argon for 20 minutes and the reaction thereto thereby. This mixture between CH ₂ Cl ₂ (100 mL) and saturated sodium carbonate (15mL) delamination. After extraction, the organic layer was separated and the aqueous layer was an additional 50mL CH ₂ Cl ₂ extracted with. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to give a yellow oil, which was subjected to flash chromatography on silica using _{2% MeOH / CH 2 Cl 2} , followed by 5-10% 2M NH ₃ in MeOH /CH ₂ Cl ₂ gave a yellow semi-solid (100 mg, 69.9%). ¹ H-NMR (DMSO-d ₆ ) δ 7.75 (d, J = 3.3 Hz, 1H), 7.60 (d, J = 5.1 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 7.12-7.09 (m, 1H), 6.79-6.74 (m, 2H), 6.46 (brs, 2H), 3.30-3.28 (m, 2H), 2.65-2.60 (m, 2H), 2.32-2.27 (m, 2H), 2.15 -1.98 (m, 4H), 2.09 (s, 6H). MS (ESI): 357.2 (M+1). ESI-HRMS calcd for C ₁₉ H ₂₅ N ₄ SO (MH ⁺ ): 357.1743, observed: 357.1753.

Example 26

7-Nitro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one (1) : See Example 25 for complete experimental details and spectral data. 7-Nitro-1-(2-(pyrrolidin-1-yl)ethyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one (2) :

Compound 1 (0.49g, 2.38mmol), 1- (2- chloroethyl) pyrrolidine hydrogen chloride (0.80g, 4.75mmol) and _{K 2 CO 3 (1.97g, 14.28} mmol) in dry DMF (15mL) suspension of The solution was stirred at room temperature overnight. At this point, the starting material was observed; then, 1-(2-chloroethyl)pyrrolidine hydrogen chloride (0.80 g, 4.75 mmol) and K ₂ CO ₃ (1.97 g, 14.28 mmol) were added and stirred for an additional 24 h. . The reaction was diluted with water (50 mL) and EtOAc (EtOAc) The combined ethyl acetate layer was washed with brine (2 × 50mL) and dried (Na ₂ SO _4). The solvent was evaporated and the crude product was purified by column chromatography to (2M NH ₃ in _{MeOH: CH 2 Cl 2, 2} : 98 to 5:95) to give compound 2 (0.35g, 49%) pulp. ¹ H NMR (DMSO- d ₆ ) δ 1.50-1.56 (m, 4H), 2.02-2.18 (m, 4H), 2.26-2.34 (m, 4H), 2.45-2.48 (m, 2H, merged with DMSO peak) , 2.85 (t, 2H, J = 6.6 Hz), 3.96 (brs, 2H), 7.66 (d, 1H, J = 8.7 Hz), 8.14-8.20 (m, 2H); ESI-MS (m/z, % ): 304 (MH ⁺ , 100), 233 (26).

7-Amino-1-(2-(pyrrolidin-1-yl)ethyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one (3) :

A solution of compound 2 (0.33 g, 1.087 mmol) in dry ethanol (5 mL) was taken eluting with Pd-C (~ 0.05 g) and vented with hydrogen. The flask was degassed, aerated with hydrogen (2 times) and stirred at room temperature (balloon pressure) for 3.5 h under a hydrogen atmosphere. The reaction was filtered through a pad of celite and washed with methanol (3×10 mL). The combined organic layers were evaporated to give a crude compound 3 (0.283 g, 95%). ¹ H NMR (DMSO- d ₆ ) δ 1.56-1.60 (m, 4H), 1.90-2.08 (m, 4H), 2.30-2.56 (m, 10H), 5.04 (s, 2H), 6.39 (d, 1H, J = 2.4 Hz), 6.46 (dd, 1H, J = 2.4, 9.1 Hz), 6.98 (d, 1H, J = 8.4 Hz); ESI-MS (m/z, %) 274 (MH ⁺ , 100), 203 (36).

N-(2-Sideoxy-1-(2-(pyrrolidin-1-yl)ethyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-7-yl ) thiophene-2-carboxyindoleimine (26) :

Compound 3 (0.1g, 0.365mmol) in absolute ethanol (5mL) of a solution, compound 4 (0.2g, 0.731mmol) process, and the mixture was stirred at room temperature for 18h. The reaction was diluted with saturated NaHCO ₃ solution (25mL), and the product was extracted into _{CH 2 Cl 2 (2 × 20mL} ). The combined CH ₂ Cl ₂ layer was washed with brine (10 mL) and dried (Na ₂ SO _4). The solvent was evaporated and the crude product was purified by column chromatography to (2M NH ₃ in _{MeOH: CH 2 Cl 2, 3} : 97) to give compound 5 (0.11g, 79%) solid. ¹ H NMR (DMSO- d ₆ ) δ 1.56-1.68 (m, 4H), 1.88-2.06 (m, 2H), 2.10-2.18 (m, 2H), 2.32-2.68 (m, 10H), 6.45 (brs, 2H), 6.73 (d, 1H, J = 1.5 Hz), 7.10 (d, 1H, J = 4.2 Hz), 7.27 (d, 1H, J = 8.4 Hz), 7.61 (d, 1H, J = 5.1 Hz) , 7.74 (d, 1H, J = 3.3 Hz); ESI-MS (m/z, %) 383 (MH ⁺ , 100), 312 (52), 156 (90), 148 (76); ESI-HRMS calculation Values for C ₂₁ H ₂₇ N ₄ OS (MH ⁺ ), calc.: 383.1900, observed: 383.1894; HPLC purity 91.2%.

Example 27

7-Amino-1-(2-(pyrrolidin-1-yl)ethyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one (1) : Please See Example 26 for complete experimental details and spectral data. 1-(2-(Pyrrolidin-1-yl)ethyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-7-amine (2):

The LiAlH ₄ (2.48mL, 2.487mmol, 1.0M suspension in anhydrous THF) of the suspension of compound 1 (0.17g, 0.621mmol) treatment at 0 ℃ 2 minutes at dry THF (5mL). The reaction was brought to room temperature and stirred for 18 h. The reaction was quenched with water (0.1 mL), 2N NaOH solution (0.1 mL) and water (0.1 mL). After stirring at room temperature for 30 min, the reaction was filtered, washed with _{CH 2 Cl 2 (3 × 15mL} ). The combined organic layers were evaporated and the crude product was purified by column chromatography to (2M NH ₃ in _{MeOH: CH 2 Cl 2, 5} : 95) to give compound 2 (0.15g, 94%) thick slurry. ¹ H NMR (DMSO- d ₆ ) δ 1.40-1.50 (m, 2H), 1.56-1.70 (m, 6H), 2.40-2.60 (m, 8H), 2.74 (t, 2H, J = 5.1 Hz), 3.07 (t, 2H, J = 7.5 Hz), 4.53 (s, 2H), 6.30-6.34 (m, 2H), 6.65 (d, 1H, J = 8.1 Hz); ESI-MS (m/z, %) 260 (MH ⁺ , 100), 189 (85).

N-(1-(2-(pyrrolidin-1-yl)ethyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-yl)thiophene-2-carboxylate Indoleamine (27) :

Compound 2 (0.13g, 0.501mmol) in absolute ethanol (5mL) of a solution, compound 3 (0.28g, 1.002mmol) process, and the mixture was stirred at room temperature for 16h. The reaction was diluted with saturated HCO ₃ solution (25mL), and the product was extracted into _{CH 2 Cl 2 (2 × 20mL} ). The combined CH ₂ Cl ₂ layer was washed with brine (10 mL) and dried (Na ₂ SO _4). The solvent was evaporated and the crude product was purified by column chromatography to (2M NH ₃ in _{MeOH: CH 2 Cl 2, 5} : 95) to give compound 27 (0.15g, 83%) solid. ¹ H NMR (DMSO- d ₆ ) δ 1.48-1.56 (m, 2H), 1.60-1.68 (m, 6H), 2.40-2.55 (m, 4H), 2.58 (t, 2H, J = 6.6 Hz), 2.62 -2.70 (m, 2H), 2.82-2.90 (m, 2H), 3.19 (t, 2H, J = 7.5 Hz), 6.29 (s, 2H), 6.60-6.66 (m, 2H), 6.89 (d, 1H) , J = 9.0 Hz), 7.07 (dd, 1H, J = 3.9, 4.8 Hz), 7.57 (d, 1H, J = 4.8 Hz), 7.70 (d, 1H, J = 3.6 Hz); ESI-MS (m) / z,%) 369 (MH +, 77), 272 (100); ESI-HRMS calcd for _{C 21 H 29 N 4 S (} MH +), calculated: 369.2107, observed: 369.2121; HPLC purity 98.8 %area.

Example 28

1-(2-(Dimethylamino)ethyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-7-amine

The 1M LiAlH ₄ in THF (1.82mL, 1.82mmol) of the suspension was cooled to 0 ℃, then 7--1- (2- (dimethylamino) ethyl) -4,5-dihydro -1H-benzo[b]azepine-2(3H)-one (225 mg, 0.91 mmol) was added dropwise in 10 mL of THF (see the experimental procedure of Synthesis Example 25). The suspension was stirred at room temperature overnight. The mixture was then cooled to 0 ° C and treated with 1 mL of 1N NaOH dropwise with stirring. After stirring for 20 minutes, the suspension was treated Na ₂ SO _4. The suspension was filtered, the solid was 50mL 10% 2M NH ₃ in MeOH / CH ₂ Cl ₂ rinse. The filtrate was concentrated and the dark residue was applied to flash chromatography on silica, using 5% 2M NH ₃ in MeOH / CH ₂ Cl ₂ to give a dark viscous oil (75mg, 35.4%). ¹ H-NMR (CDCl ₃ ) δ 6.80-6.78 (m, 1H), 6.52-6.48 (m, 2H), 3.40 (brs, 2H), 3.21-3.17 (m, 2H), 2.87-2.83 (m, 2H) ), 2.70-2.66 (m, 2H), 2.47-2.43 (m, 2H), 2.27 (s, 6H), 1.72-1.64 (m, 2H), 1.59-1.55 (m, 2H). MS (ESI): 234.2 (M+1).

N-(1-(2-(Dimethylamino)ethyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-yl)thiophene-2-carboxyindole Imine amine dihydrogen chloride

1-(2-(Dimethylamino)ethyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-7-amine (65 mg, 0.28 mmol) in 5 mL EtOAc The solution was treated with methylthiophene-2-carbomine thiocarboxylate hydrogen iodide (159 mg, 0.56 mmol) and stirred at room temperature overnight. CH ₂ Cl ₂ (20mL) was diluted to promote, and the mixture was bubbled with argon for 20 minutes and the reaction thereto thereby. This mixture between CH ₂ Cl ₂ (100 mL) and saturated sodium carbonate (15mL) delamination. After extraction, the organic layer was separated and the aqueous layer was an additional 50mL CH ₂ Cl ₂ extracted with. The combined organic layers were dried over magnesium sulfate, filtered and concentrated to give a yellow oil, which was subjected to flash chromatography on silica using _2% MeOH / CH 2 Cl 2 then 5-10% 2M NH ₃ in MeOH / CH ₂ Cl ₂ gave a yellow semi-solid. The residue was taken up in CH ₂ Cl ₂ and converted to dihydrochloride with HCl. A brown solid (35 mg, 36.5%) was obtained. ¹ H-NMR (CD ₃ OD) δ 8.05-8.02 (m, 2H), 7.37-7.21 (m, 4H), 3.64 (t, J = 6.3 Hz, 2H), 3.39 (t, J = 6.0 Hz, 2H) ), 3.08-3.05 (m, 2H), 2.95-2.85 (m, 2H), 2.94 (s, 6H), 1.90-1.80 (m, 2H), 1.70-1.60 (m, 2H). MS (ESI): 343.2 (M+1). ESI-HRMS calculated for C ₁₉ H ₂₇ N ₄ S (MH ⁺ ): 343.1950, observed: 343.1949.

Example 29

3-(3,4-dihydroquinolin-1(2H)-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

a solution of 1,2,3,4-tetrahydroquinoline (1.0 mL, 7.94 mmol) in 30 mL of 1,2-dichloroethane as 3-tertyloxypyrrolidine-1-carboxylic acid tert-butyl ester (2.94 g, 15.87 mmol) was treated with EtOAc EtOAc (EtOAc (EtOAc) The suspension was stirred at room temperature for 1 day. The mixture was then cooled to 0 ° C, quenched with 20 mL 1 N NaOH and stirred for 20 min. The suspension was extracted with CH ₂ Cl ₂ to 2 × 100mL. The organic layer was washed with EtOAc EtOAc (EtOAc m.. . ¹ H-NMR (CDCl ₃ ) δ 7.07 (pseudo t, J = 7.2 Hz, 1H), 6.97 (d, J = 7.2 Hz, 1H), 6.69 (d, J = 8.1 Hz, 1H), 6.62 (pseudo t , J=7.5Hz, 1H), 4.44-4.40(m,1H), 3.63-3.20(m,6H), 2.75(t,J=6.3Hz,2H),2.13-2.08(m,2H),1.94- 1.90 (m, 2H), 1.48 (s, 9H). MS (ESI): 303.2 (M+1).

3-(6-bromo-3,4-dihydroquinolin-1(2H)-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

A solution of 3-(3,4-dihydroquinolin-1(2H)-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (1.86 g, 6.15 mmol) in 15 mL of DMF was cooled to 0 ° C, then dripped NBS (1.09 g, 6.15 mmol) was added in 15 mL DMF. The reaction was stirred at 0 ° C for 1.5 hours and then treated with 100 mL H ₂ O. This suspension was treated with 2 x 150 mL EtOAc. The combined organic layers were washed with brine (3×20 mL) dried over sodium sulfate. The residue was flash chromatographed on silica gel eluting with 15% EtOAc/hexane to afford viscous oil ( 1.50 g, 63.8%). ¹ H-NMR (CDCl ₃ ) δ 7.13 (d, J = 9.0 Hz, 1H), 7.07 (brs, 1H), 6.55 (d, J = 9.0 Hz, 1H), 4.35 - 4.33 (m, 1H), 3.58 -3.18 (m, 6H), 2.71 (t, J = 6.3 Hz, 2H), 2.11-2.04 (m, 2H), 1.91-1.87 (m, 2H), 1.47 (s, 9H). MS (ESI): 325.1 and 327.1 (M+1, 100%).

3-(6-Amino-3,4-dihydroquinolin-1(2H)-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

The _{Pd 2 (dba) 3 (46mg} , 0.05mmol) in 2mL of anhydrous THF suspension to _{PtBu 3 (600μL of a 10%} wt solution in hexane, 0.2mmol) and stirred at room temperature for 5 minutes. A solution of tert-butyl 3-(6-bromo-3,4-dihydroquinolin-1(2H)-yl)pyrrolidine-1-carboxylate (381 mg, 1.00 mmol) followed by hexamethyldi Lithium decane alkoxide (2.0 mL of 1 M solution in THF, 2.0 mmol). The dark brown suspension obtained was heated at 95 ° C for 1.5 hours. The mixture was cooled to room temperature and treated with 8 mL of 1M tetrabutyl ammonium fluoride solution in THF and then stirred at room temperature for 20 min. The mixture was partitioned between Et ₂ O (100 mL) and H ₂ O (20 mL). After extraction, the organic layer was separated and the aqueous layer was extracted once more with Et ₂ O (50 mL). The combined organic portions were dried over sodium sulfate, filtered and concentrated to give a dark brown residue. The residue was subjected to flash chromatography on silica, using 2.5% 2M NH ₃ in MeOH / CH ₂ Cl ₂ to give a viscous dark brown residue (295mg, 93.1%). ¹ H-NMR (CDCl ₃ ) δ 6.59-6.44 (m, 3H), 4.35-4.23 (m, 1H), 3.59-3.11 (m, 8H), 2.69 (t, J = 6.3 Hz, 2H), 2.09- 2.04 (m, 2H), 1.93-1.87 (m, 2H), 1.47 (s, 9H). MS (ESI): 318.2 (M+1, 100%).

Third butyl-3-(6-(thiophene-2-carboxyindoleamine)-3,4-dihydroquinolin-1(2H)-yl)pyrrolidine-1-carboxylate

A solution of tert-butyl 3-(6-amino-3,4-dihydroquinolin-1(2H)-yl)pyrrolidine-1-carboxylate (210 mg, 0.66 mmol) in 12 mL of EtOH Methyl thiophene-2-carboindole thiocarboxylate hydrogen iodide (377 mg, 1.32 mmol) was treated and stirred at room temperature overnight. This mixture was argon into the pump for 20 minutes then layered in between CH ₂ Cl ₂ (100 mL) and saturated sodium carbonate (20mL). The aqueous layer was an additional 50mL CH ₂ Cl ₂ extracted with. The combined organic layers were dried over magnesium sulfate, filtered and concentrated to give a dark yellow oil which was subjected to flash chromatography on silica using _{2% MeOH / CH 2 Cl 2} , then 2.5% 2M NH ₃ in MeOH / CH ₂ Cl ₂ gave a yellow solid (168 mg, 59.6%). ¹ H-NMR (DMSO-d ₆ ) δ 7.68 (d, J = 3.3 Hz, 1H), 7.57 (d, J = 5.1 Hz, 1H), 7.07 (dd, J = 3.9, 5.1 Hz, 1H), 6.73 (d, J=8.7 Hz, 1H), 6.59-6.52 (m, 2H), 6.34 (brs, 2H), 4.46-4.34 (m, 1H), 3.51-3.10 (m, 6H), 2.69 (t, J = 6.3 Hz, 2H), 2.08-1.99 (m, 2H), 1.85-1.78 (m, 2H), 1.41 (s, 9H). MS (ESI): 427.2 (M+1, 100%).

N-(1-(pyrrolidin-3-yl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2- Carboxylium imine guanamine dihydrogen chloride

Tert-butyl-3-(6-(thiophene-2-carboxyindoleamine)-3,4-dihydroquinolin-1(2H)-yl)pyrrolidine-1-carboxylate (150 mg , 0.35 mmol) in 5 mL of methanol, treated with 10 mL of 1N HCl and then heated at 70 ° C for 30 min. The solution was concentrated and dried under reduced pressure to give a yellow solid. The solid was _{5% MeOH / 95% Et 2} O mashed. The yellow solid was collected and dried under reduced pressure. Yield: 125 mg (89.3%). ¹ H-NMR (DMSO-d ₆ ) δ 11.23 (s, 1H), 9.78 (brs, 1H), 9.65 (brs, 1H, 9.59 (brs, 1H), 8.61 (s, 1H), 8.15-8.14 (m) , 2H), 7.36 (pseudo t, J=4.5Hz, 1H), 7.09-6.88 (m, 3H), 4.76-4.66 (m, 1H), 3.39-3.06 (m, 6H), 2.72 (t, J = 5.4 Hz, 2H), 2.16-2.01 (m, 2H), 1.87-1.83 (m, 2H). MS (ESI): 327.2 (M+1). ESI-HRMS calculated for C ₁₈ H ₂₃ N ₄ S (MH ⁺ ): 327.1637, observed: 327.1649.

Example 30

1-(2-(Dimethylamino)ethyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one

6-Nitro-3,4-dihydroquinolin-2(1H)-one ¹ (1.5 g, 7.80 mmol), 2-chloro-N,N-dimethylethylamine hydrogen chloride (2.25 g, 15.60 mmol And a suspension of potassium carbonate (6.47 g, 46.80 mmol) in 25 mL of DMF and stirred at room temperature for 3 days. After the mixture was poured into 20mL H ₂ O 150 mL then extracted with EtOAc in ×. 3. The combined organic portions were washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was subjected to flash chromatography on silica gel using 5% 2M NH ₃ in MeOH / CH ₂ Cl ₂ to give a viscous yellow oil (1.5g, 73.2%). ¹ H-NMR (CDCl ₃ ) δ 8.14 (dd, J = 2.4, 9.0 Hz, 1H), 8.06 (d, J = 2.4 Hz, 1H), 7.15 (d, J = 9.0 Hz, 1H), 4.09 (t , J = 7.5 Hz, 2H), 3.03 - 2.98 (m, 2H), 2.73 - 2.68 (m, 2H), 2.51 (t, J = 7.5 Hz, 2H), 2.31 (s, 6H). MS (ESI): 364.1 (M+1)

1. Devita et al, WO03/045313

N,N-Dimethyl-2-(6-nitro-3,4-dihydroquinolin-1(2H)-yl)ethylamine

Cooling a solution of 1-(2-(dimethylamino)ethyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (1.0 g, 3.80 mmol) in 10 mL THF It was treated with a solution of 1 M borane in THF (21.5 mL, 21.50 mmol). The solution was heated to reflux for 6 hours and then stirred at room temperature for 1 day. The mixture was then cooled to 0 ° C and quenched with methanol (5 mL). The mixture was concentrated, dissolved in MeOH (20 mL)EtOAc. The reaction was concentrated, and the residue was subjected to silica gel chromatography using a Biotage following _{gradient: 1-10% 2M NH 3 2 Cl} 2 to give a viscous oil (598mg, 63.1%) in MeOH / CH. ¹ H-NMR (CDCl ₃ ) δ 7.96 (dd, J = 2.7, 9 Hz, 1H), 7.85 (d, J = 2.1 Hz, 1H), 6.48 (d, J = 9 Hz, 1H), 3.50 - 3.43 (m) , 4H), 2.78 (t, J = 6.3 Hz, 2H), 2.50 (t, J = 7.5 Hz, 2H), 2.29 (t, 6H), 1.99-1.94 (m, 2H). MS (ESI): 250.2 (m+1).

Methyl (2-(6-nitro-3,4-dihydroquinolin-1(2H)-yl)ethyl)aminecarboxylic acid phenyl ester

The N, N- dimethyl-2- (6-nitro-3,4-dihydro-quinoline -1 (2H) - yl) solution of ethylamine (500mg, 2.01mmol) in 10mL CH ₂ Cl _2, the Treatment with phenyl chloroformate (378 μL, 3.01 mmol) was added dropwise. The reaction was stirred at room temperature for 17 h, then partitioned between (20mL) in CH ₂ Cl ₂ 100mL and 1N NaOH. After extraction, the organic layer was separated, dried over sodium sulfate, filtered and concentrated to give a yellow residue. The residue was subjected to flash chromatography on silica, using 20% EtOAc / CH ₂ Cl ₂ to give a yellow residue (610mg, 85.4%). ¹ H-NMR (CDCl ₃ ) δ 7.99-7.92 (m, 1H), 7.87 (d, J = 2.1 Hz, 1H), 7.39-7.33 (m, 2H), 7.23-7.19 (m, 1H), 7.06- 7.01 (m, 2H), 6.69 (m, 1H), 3.67-3.52 (m, 4H), 3.48 (t, J = 5.7 Hz, 2H), 3.14 and 3.07 (2 x s, 3H), 2.79 (t, J = 6.3 Hz, 2H), 1.99-1.96 (m, 2H). MS (ESI): 356.2 (M+1).

2-(6-Amino-3,4-dihydroquinolin-1(2H)-yl)ethyl(methyl)aminecarboxylic acid Phenyl ester

Phenylmethyl 2-(6-nitro-3,4-dihydroquinolin-1(2H)-yl)ethyl)aminecarboxylate (500 mg, 1.41 mmol) and palladium on activated carbon (10%) A suspension of 1:1 mixture of THF/EtOH (20 mL) was stirred in a hydrogen balloon for 4.5 hours. This suspension was filtered through a pad of celite. The filter pad was rinsed with 25 mL of methanol and the filtrate was concentrated to give a dark viscous oil. This crude product was used without further purification (460 mg, quantitative). ¹ H-NMR (CDCl ₃ ) δ 7.39-7.34 (m, 2H), 7.22-7.17 (m, 1H), 7.12-7.08 (m, 2H), 6.61-6.42 (m, 3H), 3.61-3.45 (m) , 4H), 3.26 (t, J = 6.0 Hz, 2H), 3.20 (brs, 2H), 3.13 and 3.06 (2 xs, 3H), 2.70 (t, J = 6.3 Hz, 2H), 1.96-1.87 (m , 2H). MS (ESI): 326.2 (M+1).

Methyl (2-(6-(thiophene-2-carboxyindoleamine)-3,4-dihydroquinolin-1(2H)-yl)ethyl)amine carboxylic acid phenyl ester

A solution of phenyl 2-(6-amino-3,4-dihydroquinolin-1(2H)-yl)ethyl(methyl)aminecarboxylate (445 mg, 1.37 mmol) in 20 mL of EtOAc The thiophene-2-carboquinone thiocarboxylate hydrogen iodide (780 mg, 2.73 mmol) was treated and stirred at room temperature overnight. This mixture was argon into the pump for 20 minutes then layered in between CH ₂ Cl ₂ (100 mL) and saturated sodium carbonate (20mL). After extraction, the organic layer was separated and the aqueous layer was an additional 100mL CH ₂ Cl ₂ extracted with. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a dark oil which was subjected to flash chromatography on silica using 2.5% MeOH / CH ₂ Cl ₂ followed by 2.5-7.5% 2M NH ₃ in MeOH / CH ₂ Cl ₂ gave a yellow-brown solid (400 mg, 67.2%). ¹ H-NMR (DMSO-d ₆ ) δ 7.68 (brs, 1H), 7.58 (d, J = 5.1 Hz, 1H), 7.42 - 7.34 (m, 2H), 7.24 - 7.18 (m, 1H), 7.11 7.03 (m, 3H), 6.68 (d, J = 9.0 Hz, 1H), 6.57-6.51 (m, 2H), 6.29 (brs, 2H), 3.58-3.44 (m, 4H), 3.32-3.27 (m, 2H), 3.09 and 2.97 (2 xs, 3H), 2.73-2.65 (m, 2H), 1.90- 1.83 (m, 2H). MS (ESI): 435.2 (M+1, 100%).

N-(1-(2-(methylamino)ethyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboxyindoleimine guanamine dihydrogen chloride

Methyl (2-(6-(thiophene-2-carboindoleamine)-3,4-dihydroquinolin-1(2H)-yl)ethyl)) phenyl ester (380 mg, 0.87 mmol) ) in ethanol 15mL solution to NaOH (350mg, 8.70mmol) process, then H ₂ O (8mL) process. The mixture was heated to reflux for 6 hours. The solution was concentrated and then partitioned between CH ₂ Cl ₂ (100 mL) and brine (20mL). After extraction, the organic layer was separated and the aqueous layer was extracted with CH ₂ Cl ₂ (100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was subjected to flash chromatography on silica, using 5% 2M NH ₃ in MeOH / CH ₂ Cl ₂ to give a yellow solid 30 (155mg, 56.8%). The free base was dissolved in MeOH and by 1M HCl was added to Et ₂ O is converted to dihydrochloride salt. ¹ H-NMR (CD ₃ OD) δ 7.98-7.95 (m, 2H), 7.31-7.28 (m, 1H), 7.05 (dd, J = 2.4, 8.7 Hz, 1H), 6.97 (d, J = 2.4 Hz) , 1H), 6.81 (d, J = 8.7 Hz, 1H), 3.62 (t, J = 6.6 Hz, 2H), 3.34 (t, J = 5.4 Hz, 2H), 3.20 (t, J = 6.9 Hz, 2H) ), 2.78 (t, J = 6.0 Hz, 2H), 2.72 (s, 3H), 1.99 - 1.92 (m, 2H). MS (ESI): 315.2 (M+1). ESI-HRMS calculated for C ₁₇ H ₂₃ N ₄ S (MH ⁺ ): 315.1637, observed: 315.1629.

Example 31

3-(1-methylpiperidin-4-yl)-5-nitroindol-2-one (2) :

A solution of compound 1 (0.5 g, 2.806 mmol), N-methyl-4-piperidinone (0.69 mL, 5.613 mmol) and pyrrolidine (0.7 mL, 8.420 mmol) The reaction was brought to room temperature, diluted with water (20mL) and the product was extracted into _{CH 2 Cl 2 (2 × 25mL} ). The combined CH ₂ Cl ₂ layer was washed with brine (10 mL) and dried (Na ₂ SO _4). The solvent was evaporated, and the crude product was purified by column chromatography to (2M NH ₃ in _{MeOH: CH 2 Cl 2, 2.5} : 97.5) to give compound 2 (0.2g, 26%) solid. ¹ H NMR (DMSO- d ₆ ) δ 11.05 (s, 1H), 8.17 (dd, 1H, J = 2.1, 8.5 Hz), 8.09 (s, 1H), 6.99 (d, 1H, J = 8.7 Hz), 3.59 (d, 1H, J = 3.6 Hz), 2.77-2.70 (m, 2H), 2.09 (s, 3H), 2.05-1.96 (m, 1H), 1.84-1.74 (m, 2H), 1.54-1.36 ( m, 4H); ESI-MS (m/z, %): 276 (MH ⁺ , 100)

5-amino-3-(1-methylpiperidin-4-yl)porphyrin-2-one (3) :

A solution of compound 2 (0.18 g, 0.654 mmol) in dry ethanol (5 mL) was taken eluted with Pd-C (~ 0.02 g) and vented with hydrogen. The reaction was stirred at room temperature under a hydrogen atmosphere (balloon pressure) overnight (16 h). The reaction was filtered through a pad of celite and washed with methanol (3×10 mL). The combined organic layers were evaporated and the crude product was purified by column chromatography to (2M NH ₃ in _{MeOH: CH 2 Cl 2, 1} : 9) to give compound 3 (0.08g, 50%) foam. ¹ H NMR (DMSO- d ₆ ) δ 9.89 (s, 1H), 6.57 (s, 1H), 6.48 (d, 1H, J = 8.1 Hz), 6.37 (d, 1H, J = 8.1 Hz), 4.64 ( s, 2H), 2.78-2.67 (m, 2H), 2.09-2.04 (m, 4H), 1.87-1.70 (m, 3H), 1.61-1.52 (m, 2H), 1.37-1.26 (m, 2H); ESI-MS (m/z, %): 246 (MH ⁺ , 100)

N-(3-(1-methylpiperidin-4-yl)-2-oxooxyporphyrin-5-yl)thiophene-2-carboxyindoleimide amide (31) :

Compound 3 (0.07g, 0.285mmol) in absolute ethanol (3mL) the solution of compound 4 (0.16g, 0.570mmol) at room temperature, and the mixture stirred for 2 days the resulting sum. The reaction was diluted with saturated NaHCO ₃ solution (20mL), and the product was extracted into _{CH 2 Cl 2 (2 × 15mL} ). The combined organic layers were washed with brine (15mL) and dried (Na ₂ SO _4). The solvent was evaporated and the crude product was purified by column chromatography to (2M NH ₃ in _{MeOH: CH 2 Cl 2, 1} : 9) to give compound 31 (0.075g, 75%) solid. ¹ H NMR (DMSO- d ₆ ) δ 10.19 (s, 1H), 7.71 (d, 1H, J = 3.3 Hz), 7.59 (d, 1H, J = 4.5 Hz), 7.09 (t, 1H, J = 4.5) Hz), 6.75-6.65 (m, 3H), 6.34 (brs, 2H), 2.74 (t, 2H, J = 10.5 Hz), 2.56-2.46 (m, 1H, merged with DMSO peak), 2.10 (s, 3H) ), 1.90-1.75 (m, 3H), 1.58-1.32 (m, 4H); ESI-MS (m/z, %): 355 (MH ⁺ , 51), 178 (100); For C ₁₉ H ₂₃ N ₄ OS (MH ⁺ ), calcd.: 355.1587; observed: 355.1580; HPLC purity 98.34%.

Example 32

1-(2-(Dimethylamino)ethyl)-3,4-dihydroquinolin-2(1H)-one (2) :

The 1 (4g, 27.179mmol) in anhydrous DMF (50mL) solution of the compound to _{K 2 CO 3 (11.26g, 81.538mmol} ) processing, and then 2-chloro - N, N- dimethyl-ethanamine hydrochloride (4.30 g, 29.897 mmol) was treated at room temperature. The resulting mixture was stirred at 85 ° C for 2.5 days. The reaction was taken to room temperature, diluted with water (250 mL) and EtOAc (EtOAc) The combined organic layers were washed with brine (25mL) and dried (Na ₂ SO _4). The solvent was evaporated and the crude product was purified by column chromatography to (2M NH ₃ in _{MeOH: CH 2 Cl 2, 5} : 95) to give compound 2 (2.2g, 37%) pulp. ¹ H NMR (DMSO- d ₆ ) δ 7.27-7.19 (m, 2H), 7.12 (d, 1H, J = 8.1 Hz), 6.98 (t, 1H, J = 6.3 Hz), 3.96 (t, 2H, J) = 7.5 Hz), 2.82 (t, 2H, J = 7.8 Hz), 2.51 (t, 2H, J = 7.8 Hz), 2.37 (t, 2H, J = 7.2 Hz), 2.18 (s, 6H); MS ( ESI) (m/z, %): 218 (MH ⁺ , 2), 71 (36), 58 (100).

2-(3,4-Dihydroquinolin-1(2H)-yl) -N , N -dimethylethylamine (3) :

The LiAlH ₄ (39.39mL, 39.397mmol, 1M solution in THF) of the solution of compound 2 (2.15g, 9.849mmol) treated at 0 ℃ in dry THF (25mL). The reaction was brought to room temperature and stirred overnight (18 h). The reaction was quenched with water (1.5 mL), 2N NaOH solution ( 1.5 mL) and water ( 1.5 mL). After stirring at room temperature for 30 min, the reaction was filtered, washed with _{CH 2 Cl 2 (4 × 20mL} ). The combined organic layers were evaporated and the crude product was purified by column chromatography to (2M NH ₃ in _{MeOH: CH 2 Cl 2, 2} : 98 to 5:95) to give compound 3 (0.95g, 47%) pulp. ¹ H NMR (DMSO- d ₆ ) δ 6.93 (t, 1H, J = 8.1 Hz), 6.83 (d, 1H, J = 7.2 Hz), 6.51 (d, 1H, J = 8.1 Hz), 6.43 (t, 1H, J = 7.8 Hz), 3.33 - 3.24 (m, 4H), 2.64 (t, 2H, J = 6.3 Hz), 2.36 (t, 2H, J = 7.5 Hz), 2.17 (s, 6H), 1.85- 1.77 (m, 2H); MS (ESI) (m/z, %) 205 (MH ⁺ , 22), 160 (100), 132 (65).

N , N -Dimethyl-2-(7-nitro-3,4-dihydroquinolin-1(2H)-yl)ethylamine (4):

Compound 3 (0.87g, 4.285mmol) in concentrated H ₂ SO ₄ (10mL) of solution of fuming _{HNO 3 (0.2mL, 4.285mmol, 90} %) treated dropwise at 0 deg.] C 10 minutes, and at the same temperature Stir for an additional 20 minutes. The reaction was diluted with water (50mL), basified to pH ~ 10, using 2N NaOH solution and the product was extracted into _{CH 2 Cl 2 (3 × 20mL} ). The combined organic layers were washed with brine (15mL) and dried (Na ₂ SO _4). The solvent was evaporated and the crude product was purified by column chromatography to (2M NH ₃ in _{MeOH: CH 2 Cl 2, 2.5} : 97.5 to give compound 4 (0.85g, 80%), including some dinitro derivatives, after The stage is separated.

1-(2-(Dimethylamino)ethyl)-1,2,3,4-tetrahydroquinolin-7-amine (5) :

A solution of compound 4 (0.8 g, 3.208 mmol) in dry ethanol (20 mL) was taken eluting with Pd-C (~0.08 g) and vented with hydrogen. The reaction was stirred at room temperature under a hydrogen atmosphere for 3 h. The reaction was filtered through a pad of celite and washed with methanol (3×20 mL). The combined organic layers were evaporated and the crude product was purified by column chromatography to (2M NH ₃ in _{MeOH: CH 2 Cl 2, 5} : 95) to give Compound 5 (0.6g, 86%).

N-(1-(2-(Dimethylamino)ethyl)-1,2,3,4-tetrahydroquinolin-7-yl)thiophene-2-carboximine amide (36) :

Compound 5 (0.55g, 2.507mmol) in absolute ethanol (10 mL) of the solution, compound 6 (1.43g, 5.015mmol) at room temperature, and the mixture thus obtained to stir overnight (16h). The reaction was diluted with saturated NaHCO ₃ solution (50mL), and the product was extracted into _{CH 2 Cl 2 (2 × 25mL} ). The combined organic layers were washed with brine (15mL) and dried (Na ₂ SO _4). The solvent was evaporated and the crude product was purified by column chromatography to (2M NH ₃ in _{MeOH: CH 2 Cl 2, 3} : 97) to give compound 32 (0.5g, 61%) solid. ¹ H NMR (DMSO- d ₆ ) δ 7.69 (dd, 1H, J = 0.9, 3.6 Hz), 7.57 (dd, 1H, J = 0.9, 5.1 Hz), 7.07 (dd, 1H, J = 3.9, 5.1 Hz) ), 6.78 (d, 1H, J = 7.8 Hz), 6.25 (brs, 2H), 6.01-5.98 (m, 2H), 3.32-3.25 (m, 4H), 2.38 (t, 2H, J = 6.9 Hz) , 2.16 (s, 6H), 1.86-1.80 (m, 2H); ESI-MS (m/z, %): 329 (MH ⁺ , 100), 258 (40); ESI-HRMS calculated for C ₁₈ H ₂₅ N ₄ S (MH ⁺ ), calcd.: 329.1794; observed:

Example 33

9-Amino-1-(2-(dimethylamino)ethyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one (2):

1- (2- (dimethylamino) ethyl) -1H- 9-nitro-4,5-dihydro-benzo [b] Boom nitrogen -2 (3H) - one (100mg, 0.361mmol Stirred to a mixture of ethanol (4 mL) and THF (3 mL). To this solution, palladium-carbon, 10 wt% (40 mg) solid was added. The black suspension was stirred in hydrogen for 3 h. When the TLC analysis indicated that the starting material had been consumed, the reaction mixture was filtered through a pad of celite and washed with methanol. The filtrate was concentrated and chromatographed on 10% 2N NH ₃ / MeOH in dichloromethane on silica. Yield 90 mg (quantitative). ¹ H NMR (DMSO-d ₆ ) δ 6.86 (d, 1H, J = 8.1 Hz), 6.53 (d, 1H, J = 3.0 Hz), 6.38 (dd, 1H, J = 8.1, 3.0 Hz), 5.02 ( Brs, 2H), 2.50 (m, 2H), 2.25 (m, 2H), 1.8-2.2 (m, 10H); ESI-MS (m/z, %): 248 (MH+, 58), 203 (100)

N-(1-(2-(dimethylamino)ethyl)-2-yloxy-2,3,4,5-tetrahydro-1H-benzo[b]azepine-9-yl) Thiophene-2-carboxyindoleamide (33):

9-Amino-1-(2-(dimethylamino)ethyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one (with stirring) A solution of 85 mg, 0.344 mmol) in EtOH (6 mL) was added methyl thiophene-2-carbophthalide thiocarboxylate hydrogen iodide (196 mg, 0.687 mmol). The resulting suspension was stirred at room temperature overnight. The reaction mixture was diluted with _{Na 2 CO 3 (aq, sat} ) and dichloromethane (3x) and extracted. The combined organic phase was dried, filtered and concentrated and chromatographed to 2-5% 2M NH ₃ / MeOH in dichloromethane, to give the product look. Yield: 87 mg, 71%. ¹ H NMR (DMSO-d ₆ ) δ 7.75 (d, 1H, J = 3.3 Hz, 7.61 (d, 1H, J = 4.5 Hz), 7.16 (d, 1H, J = 7.8 Hz) ), 7.10 (m, 1H), 6.82 (s, 1H), 6.66 (d, 1H, J = 8.1 Hz), 6.46 (brs, 2H), 2.65 (m, 3H), 2.28 (m, 3H), 2.17 (m, 2H), 1.9-2.15 (m, 8H). ESI-MS (m/z, %): 357 (MH+, 100), 312 (48), 156 (38), 148 (31)

Example 34

1-(2-(Dimethylamino)ethyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (3):

6-Nitro-3,4-dihydroquinolin-2(1H)-one (5 g, 25.61 mmol) and 2-chloro-N,N-dimethylethylamine hydrogen chloride (7.38 g, 51.23 mmol) A round bottom flask was weighed and stirred in DMF (50 mL). Potassium carbonate (21.59 g, 156.2 mmol) was added to this solution/suspension. The resulting suspension was stirred at room temperature overnight. The reaction mixture was poured into ice water (150 mL)EtOAc. The combined organic phases were washed with water (1x) and brine (1x). The organic phase was dried over sodium sulfate, filtered and concentrated. The obtained residue was chromatographed on of 0-20% (2M NH ₃ in MeOH) in 1: 1 methylene chloride and ethyl acetate, to give a yellow solid. Yield: 5.8 g, 84%. ¹ H NMR (CDCl ₃ ) δ 8.14 (dd, 1H, J = 9.0, 3.0 Hz) 8.06 (d, 1H, J = 3.0 Hz), 7.16 (d, 1H, J = 9.0 Hz), 4.08 (t, 1H, J = 7.5 Hz), 3.00 (t, 1H, J = 7.5 Hz), 2.70 (t, 1H, J = 7.5 Hz); 2.51 (t, 1H, J = 7.5 Hz) , 2.31 (s, 6H)

Methyl (2-(6-nitro-2-oxooxy-3,4-dihydroquinolin-1(2H)-yl)ethyl)aminecarboxylic acid phenyl ester (5):

1-(2-(Dimethylamino)ethyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (1.16 g, 4.40 mmol) was dissolved in two at room temperature Methyl chloride (20 mL) was placed in a round bottom flask. The solution was cooled to 0 ° C and phenyl chloroformate (0.829 mL, 6.61 mmol) was slowly added to prevent excessive exotherm. The reaction mixture was then warmed to room temperature and stirred overnight. The reaction mixture was then diluted with dichloromethane and quenched with dilute NaOH (~0.5M). The aqueous phase was extracted with dichloromethane (3x). The residue obtained was chromatographed on 50-100% ethyl acetate in hexane. Yield: 1.29 g, 78%. ¹ H NMR (CDCl ₃ ) δ 8.13 (dd, 1H, J = 9.0, 2.7 Hz), 8.05 (t, 1H, J = 3.3 Hz), 7.41 (m, 3H); 7.23 (m, 1H); 7.06 (m, 2H), 4.23 (m, 2H), 3.70 and 3.58 (2t, 2H, J = 7.2 Hz), 3.19 and 3.09 (2s, 3H), 3.00 (t, 2H, J) = 7.4 Hz), 2.72 (t, 2H, J = 7.4 Hz); ESI-MS (m/z, %): 392 (MNa ⁺ , 100), 370 (MH+, 28)

2-(6-Amino-2-oxo-3,4-dihydroquinolin-1(2H)-yl)ethyl(methyl)aminecarboxylate (6):

Methyl (2-(6-nitro-2-oxooxy-3,4-dihydroquinolin-1(2H)-yl)ethyl)aminecarboxylic acid phenyl ester (1.29 g, 3.49 mmol) was Ethanol (40 mL) and THF (30 mL) were stirred and dissolved in a round bottom flask. The solution was stirred at room temperature for 6 h under a hydrogen atmosphere. When TLC confirmed the completion of the reaction, the mixture was filtered over Celite, and filtrate was concentrated. The residue obtained was chromatographed on silica gel and eluted with ethyl acetate to give a white/pink foam. Yield: 990 mg, 84%. ¹ H NMR (DMSO-d ₆ ) δ 7.36 (m, 2H), 7.20 (m, 1H), 7.01 (m, 2H); 6.91 (d, 1H, J = 8.4 Hz), 6.43 (m, 2H), 4.87 (s, 2H), 4.11 and 4.03 (2m, 2H), 3.56 and 3.44 (2t, 2H, J = 6.0 Hz), 2.99 and 2.87 (2s, 3H), 2.66 (m, 2H), 2.43 (m, 2H); ESI-MS (m/z, %): 362 (MNa ⁺ , 35), 340 (MH ⁺ , 100), 202 (44)

Methyl (2-(2-oxo-6-(thiophene-2-carboxyindoleamine)-3,4-dihydroquinolin-1(2H)-yl)ethyl)amine carboxylic acid phenyl ester (8):

Methylthiophene-2-carbonium imine thiocarboxylate hydrogen iodide (1.62 g, 5.71 mmol) was weighed into a round bottom flask with a stir bar. Dissolving 2-(6-Amino-2-oxo-3,4-dihydroquinolin-1(2H)-yl)ethyl(methyl)aminecarboxylate (0.969 g, 2.85 mmol) Ethanol (50 mL) was added to the flask. The resulting suspension was stirred at room temperature overnight. When the reaction was completed, argon gas was bubbled through the reaction mixture for 1 hour, and then the mixture was neutralized with sodium carbonate (sat.aq. solution). The product was extracted with dichloromethane (3x). The combined organic phases were dried with sodium sulfate, filtered and concentrated. The residue was chromatographed (1: 1) ethyl acetate: CH ₂ Cl _2, then 10% (2M NH ₃ in methanol) in dichloromethane. Yield: 700 mg, 55%. ¹ H NMR (DMSO-d ₆ ) δ 7.91 (m, 2H), 7.38 (m, 2H), 7.26 (m, 3H), 7.04 (m, 4H), 4.23 and 4.14 (2m) , 2H), 3.63 and 3.51 (2m, 2H), 3.06 and 2.92 (2s, 3H), 2.84 (t, 2H, J = 6.9 Hz), 2.56 (t, 2H, J = 6.9 Hz); ESI-MS ( m/z,%): 449 (MH ⁺ , 100)

N-(1-(2-(methylamino)ethyl)-2-yloxy-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboxyindoleimine Amine (34):

Methyl (2-(2- oxo-6-(thiophene-2-carboxyindoleamine)-3,4-dihydroquinolin-1(2H)-yl)ethyl)amine carboxylic acid benzene The ester (700 mg, 1.56 mmol) was stirred inEtOAc (20 mL). Solid NaOH (624 mg, 15.6 mmol) was added to this suspension, followed by water (10 mL). The flask was then fitted with a condenser and heated to reflux for 2 h. When TLC analysis indicated the reaction was completed, the mixture was cooled to room temperature and diluted with water. The product with dichloromethane (3x) and extracted, and the combined organic phase was dried, filtered and concentrated, then chromatographed EtOAc in, and then at 10% 2M NH ₃ / MeOH in dichloromethane. The separation point was chopped with methanol and ether. Yield (223 mg, 43%). ¹ H NMR (DMSO-d6) δ 7.73 (d, 1H, J = 3.6 Hz), 7.59 (d, 1H, J = 5.4 Hz), 7.10 (m, 2H), 6.73 (m, 2H), 6.45 (brs) , 2H), 3.91 (t, 1H, J = 7.2 Hz), 2.81 (t, 1H, J = 7.2 Hz), 2.65 (t, 1H, J = 7.2 Hz), 2.50 (t, 1H, J = 7.2 Hz) ); ESI-MS (m/z, %): 329 (MH ⁺ , 70), 149 (100), 141 (80), 127 (96)

Example 35

6-bromo-1-(pyrrolidin-3-yl)-1,2,3,4-tetrahydroquinoline

3-(6-Bromo-3,4-dihydroquinolin-1(2H)-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (see Example 29 ; 700 mg, 1.83 mmol) in 10 mL of methanol The solution was treated with 12 mL of 1N aq. HCl. A precipitate formed when the HCl solution was added. Additional methanol (10 mL) was added to dissolve this mixture. The solution was heated to reflux for 30 minutes. The solution was concentrated and _{CH 2 Cl 2 (2 × 50mL} ) and extracted. The aqueous layer was extracted with _{CH 2 Cl 2 (2 × 100mL} ) at basified with saturated Na ₂ CO _3. The combined organics were washed with brine, dried over sodium sulfate sulfate Yield: 404 mg (78.4%). ¹ H-NMR (CDCl ₃ ) δ 7.11 (dd, J = 2.7, 9.0 Hz, 1H), 7.04 (d, J = 2.1 Hz, 1H), 6.57 (d, J = 8.7 Hz, 1H), 4.36-4. (m, 1H), 3.21 (t, J = 5.4 Hz, 2H), 3.16-2.90 (m, 4H), 2.71 (t, J = 6.3 Hz, 2H), 2.11-2.00 (m, 1H), 1.93 1.78 (m, 4H). MS (ESI): 281.1 and 283.1 (M + 1).

6-bromo-1-(1-methylpyrrolidin-3-yl)-1,2,3,4-tetrahydroquinoline

A solution of 6-bromo-1-(pyrrolidin-3-yl)-1,2,3,4-tetrahydroquinoline (200 mg, 0.71 mmol) in 7 mL of dry methanol in MeOH (37% aq. , 1.07 mmol), then treated with acetic acid (100 μL, 1.78 mmol). This solution was treated with sodium cyanohydride (67 mg, 1.07 mmol). The suspension was stirred at room temperature for 3 hours. The mixture was concentrated to dryness, and in 20mL 1N NaOH and 100mL CH ₂ Cl ₂ split-level. After extraction, the organic layer was dried over sodium sulfate, filtered and concentrated to give an oily residue which was subjected to flash chromatography on silica, using 5% 2M NH ₃ in MeOH / CH ₂ Cl _2. A yellow oil (153 mg, 72.9%) was obtained. ¹ H-NMR (CDCl ₃ ) δ 7.10 (dd, J = 2.4, 8.7 Hz, 1H), 7.04 (d, J = 2.4 Hz, 1H), 6.57 (d, J = 9.0 Hz, 1H), 4.47-4.38 (m, 1H), 3.26 (t, J = 5.7 Hz, 2H), 2.81-2.68 (m, 4H), 2.60-2.55 (m, 1H), 2.40-2.24 (m, 1H), 2.35 (s, 3H) ), 2.24 - 2.13 (m, 1H), 1.92-1.79 (m, 3H). MS (ESI): 295.1 and 297.1 (M + 1).

1-(1-methylpyrrolidin-3-yl)-1,2,3,4-tetrahydroquinolin-6-amine

A suspension of Pd ₂ (dba) ₃ (22 mg, 0.024 mmol) in 2 mL anhydrous THF was taken with &lt _{;RTI ID} =0.0&gt;&gt; The mixture was stirred at room temperature for 5 minutes, then lithium lithium hexamethyldiamine (0.95 mL of 1M solution in THF, 0.95 mmol). The dark mixture obtained was treated with 6-bromo-1-(1-methylpyrrolidin-3-yl)-1,2,3,4-tetrahydroquinoline (140 mg, 0.47 mmol) in 8 mL THF. The dark brown suspension was heated at 95 ° C for 2 hours in a sealed tube. The mixture was concentrated and treated with 5 mL of 1N HCl solution and then stirred at room temperature for 10 min. And this mixture was partitioned between _{1N NaOH CH 2 Cl 2 (100mL} ) (20mL). After extraction, the organic layer was separated and dried over sodium sulfate, filtered and concentrated to give a dark brown residue. The residue was subjected to flash chromatography on silica using _{2.5% MeOH / CH 2 Cl 2} , then 5% 2M NH ₃ in MeOH / CH ₂ Cl ₂ to give a dark brown residue (95mg, 87.2%). ¹ H-NMR (CDCl ₃ ) δ 6.59 (d, J = 8.4 Hz, 1H), 6.47 (dd, J = 2.7, 8.7 Hz, 1H), 6.42 (d, J = 2.4 Hz, 1H), 4.45 - 4.38 (m,1H), 3.28 (brs, 2H), 3.23 - 3.12 (m, 2H), 2.75-2.60 (m, 5H), 2.45-2.39 (m, 1H), 2.34 (s, 3H), 2.19-2.09 (m, 1H), 1.92-1.82 (m, 3H). MS (ESI): 232.2 (m+1).

N-(1-(1-methylpyrrolidin-3-yl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboxyindoleimine

A solution of 1-(1-methylpyrrolidin-3-yl)-1,2,3,4-tetrahydroquinolin-6-amine (80 mg, 0.35 mmol) in 8 mL of ethanol as methylthiophene-2 - Carbonium imine thiocarboxylate hydrogen iodide (197 mg, 0.69 mmol) was taken and stirred at room temperature overnight. The mixture was diluted in CH ₂ Cl ₂ (10mL), and the Argon was bubbled through the solution for 20 min. This solution was partitioned between CH ₂ Cl ₂ (100 mL) and 1 N EtOAc (20 mL). After extraction, the organic layer was separated, dried over sodium sulfate, filtered and concentrated to give a dark residue which was subjected to flash chromatography on silica using _{2.5% MeOH / CH 2 Cl 2} , then 5% 2M NH ₃ in MeOH /CH ₂ Cl ₂ . A pale brown solid. This compound was converted to the hydrogen chloride salt (95 mg, 65.6%). ¹ H-NMR (DMSO-d ₆ ) δ 7.67 (d, J = 3.3 Hz, 1H), 7.55 (d, J = 5.1 Hz, 1H), 7.08-7.06 (m, 1H), 6.70 (d, J = 8.7 Hz, 1H), 6.55-6.50 (m, 2H), 6.29 (brs, 2H), 4.46-4.37 (m, 1H), 3.21-3.15 (m, 2H), 2.74-2.69 (m, 4H), 2.50 -2.43 (m, 2H), 2.25 (s, 3H), 2.15-2.04 (m, 1H), 1.86-1.67 (m, 3H). MS (ESI): 341.2 (M+1). ESI-HRMS calcd for C ₁₉ H ₂₅ N ₄ S (MH ⁺ ): 341.1794, observed: 341.1788.

Example 36

1-(2-(Dimethylamino)ethyl)-7-nitro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one (see Example 25)

7-Nitro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one (490 mg, 2.38 mmol), 2-chloro-N,N-dimethylethylamine hydrogen chloride A suspension of (685 mg, 4.75 mmol) and potassium carbonate (1.97 g, 14.28 mmol) in 15 mL of DMF was stirred at room temperature for 1 day. TLC analysis showed that the starting material was still present. This mixture was treated with 2-chloro-N,N-dimethylethylamine hydrogen chloride (685 mg, 4.75 mmol) and potassium carbonate (1.97 g, 14.28 mmol). After the mixture was poured into 50mL H ₂ O and extracted with 2 × 100mL of ethyl acetate. The combined organic portions were washed with brine, dried over sodium sulfate, filtered and concentrated to give a dark residue. The residue was subjected to flash chromatography on silica gel using 2-5% 2M NH ₃ in MeOH / CH ₂ Cl ₂ to give a yellow viscous oil (412mg, 62.4%). ¹ H-NMR (DMSO-d ₆ ) δ 8.21 - 8.15 (m, 2H), 7.67 (d, J = 8.7 Hz, 1H), 3.92-3.90 (m, 2H), 2.87-2.83 (m, 2H), 2.27 (t, J = 6.3 Hz, 2H), 2.21-2.11 (m, 4H), 2.03 (s, 6H). MS (EI): 278.1 (M + 1).

N,N-Dimethyl-2-(7-nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)ethylamine

1-(2-(Dimethylamino)ethyl)-7-nitro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one (0.8 g, 2.88) A solution of mmol) was treated with 1M borane in THF (28.8 mL, 28. The solution was heated to reflux for 6 hours and then stirred at room temperature overnight. The mixture was then cooled to 0 ° C and quenched with methanol (20 mL). The mixture was concentrated, dissolved in MeOH (20 mL) andEtOAc. The reaction was concentrated, and the residue was subjected to silica gel chromatography using the following gradient: 1.5-5% 2M NH ₃ in MeOH / CH ₂ Cl ₂ to give a yellow oil (565mg, 74.6%). ¹ H-NMR (CDCl ₃ ) δ 7.96 (dd, J = 2.7, 8.7 Hz, 1H), 7.91 (d, J = 2.7 Hz, 1H), 6.75 (d, J = 9.0 Hz, 1H), 3.44 - 3.39 (m, 2H), 3.37-3.33 (m, 2H), 2.88-2.85 (m, 2H), 2.55-2.51 (m, 2H), 2.29 (s, 6H), 1.85-1.78 (m, 4H). MS (ESI): 264.2 (M+1).

Methyl (2-(7-nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)ethyl)aminecarboxylic acid phenyl ester

N,N-Dimethyl-2-(7-nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)ethylamine (400 mg, 1.52 mmol) The solution of 10 mL of CH ₂ Cl ₂ was added dropwise with phenyl chloroformate (286 μL, 2.28 mmol). The reaction was stirred at room temperature for 21 hours and then layered in between CH ₂ Cl ₂ (100 mL) and 1N NaOH (20mL). After extraction, the organic layer was separated, and the aqueous layer was extracted with additional CH ₂ Cl ₂ (50mL). The combined organic layers were dried with sodium sulfate, filtered and evaporated The residue was subjected to flash chromatography on silica, using CH ₂ Cl ₂ to give a yellow residue (460mg, 82.0%). ¹ H-NMR (CDCl ₃ ) δ 7.99 (dd, J = 2.7, 9.0 Hz, 1H), 7.93 (d, J = 2.7 Hz, 1H), 7.40-7.34 (m, 2H), 7.23-7.18 (m, 1H), 7.10-7.04 (m, 2H), 6.87 (dd, J = 6.3, 2.7 Hz, 1H), 3.65-3.55 (m, 4H), 3.39-3.31 (m, 2H), 3.11 and 3.05 (2 xs) , 3H), 2.88-2.85 (m, 2H), 1.85-1.65 (m, 4H). MS (ESI): 370.2 (m-1).

Phenyl 2-(7-amino-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)ethyl(methyl)aminecarboxylate

Methyl (2-(7-nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)ethyl)aminecarboxylate (450 mg, 1.22 mmol) A suspension of palladium on activated carbon (10%, 65 mg, 0.06 mmol) in 1:1 THF/EtOAc (20 mL) was stirred in a hydrogen atmosphere overnight. This suspension was filtered through a pad of celite. The filter pad was rinsed with 20 mL of methanol and the filtrate was concentrated to give a dark residue. This crude product was used without further purification (325 mg, 78.5%). ¹ H-NMR (CDCl ₃ ) δ 7.38-7.33 (m, 2H), 7.21-7.08 (m, 3H), 6.87-6.81 (m, 1H), 6.53-6.48 (m, 2H), 3.57-3.47 (m , 2H), 3.42 (brs, 2H), 3.37-3.28 (m, 2H), 3.07 and 3.00 (2 xs, 3H), 2.89-2.86 (m, 2H), 2.71-2.68 (m, 2H), 1.75- 1.60 (m, 2H), 1.63-1.50 (m, 2H). MS (ESI): 340.2 (m+1).

Methyl (2-(7-(thiophene-2-carboxyindolinamine)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)ethyl)amine Phenyl formate

Phenyl 2-(7-amino-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)ethyl(methyl)aminecarboxylate (300 mg, 0.88 mmol) A solution of 12 mL of EtOH was treated with methylthiophene-2-carbomine thiocarboxylate hydrogen iodide (504 mg, 1.77 mmol) and stirred at room temperature overnight. This mixture was argon into the pump for 20 minutes then layered in between CH ₂ Cl ₂ (100 mL) and saturated sodium carbonate (20mL). After extraction, the organic layer was separated and the aqueous layer was an additional 50mL CH ₂ Cl ₂ extracted with. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a yellow residue, which was subjected to flash chromatography on silica using 2.5% MeOH / CH ₂ Cl ₂ followed by 2.5% 2M NH ₃ in MeOH / CH ₂ Cl ₂ , after drying, a yellow solid (210 mg, 53.2%). ¹ H-NMR (DMSO-d ₆ ) δ 7.71 (dd, J = 4.5, 9.3 Hz, 1H), 7.57 (d, J = 4.8 Hz, 1H), 7.41 - 7.35 (m, 2H), 7.23-7.19 ( m,1H),7.14-7.05(m,3H), 7.00-6.97(m,1H),6.64(m,2H),6.33(brs,2H),3.59-3.44(m,2H),3.33-3.26( m, 2H), 3.06 and 2.94 (2 xs, 3H), 2.93-2.88 (m, 2H), 2.72-2.63 (m, 2H), 1.75-1.60 (m, 2H), 1.63-1.50 (m, 2H) . MS (ESI): 449.2 (M+1, 100%).

N-(1-(2-(methylamino)ethyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-yl)thiophene-2-carboxyindole Amine oxime 36

Phenyl-methyl (2-(7-(thiophene-2-carboindoleamine)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl) ethyl) carbamate (200mg, 0.45mmol) in ethanol 12mL solution to NaOH (178mg, 4.46mmol), again with H ₂ O (5mL) process. The mixture was heated to reflux for 6 hours. TLC analysis indicated the presence of starting material. At this time, NaOH (90 mg) was added and heating was continued for 1 hour. The solution was concentrated to approximately 5mL, and then partitioned between CH ₂ Cl ₂ (100 mL) and brine (20mL). After extraction, the organic layer was separated and the aqueous layer was extracted with CH ₂ Cl ₂ (50mL) again. The combined organic layers were dried with sodium sulfate, filtered and evaporated The residue was subjected to flash chromatography on silica using 2.5-10% 2M NH ₃ in MeOH / CH ₂ Cl ₂ to give a yellow solid (60mg, 40.5%). ¹ H-NMR (DMSO-d ₆ ) δ 7.70 (d, J = 3.3 Hz, 1H), 7.57 (d, J = 4.8 Hz, 1H), 7.09-7.06 (m, 1H), 6.91-6.88 (m, 1H), 6.64-6.62 (m, 2H), 6.33-6.31 (m, 2H), 3.14 (t, J = 6.3 Hz, 2H), 2.85-2.70 (m, 2H), 2.77-2.61 (m, 4H) , 2.31 (s, 3H), 1.67-1.62 (m, 2H), 1.50-1.46 (m, 2H). MS (ESI): 329.2 (M+1). ESI-HRMS calculated for C ₁₈ H ₂₅ N ₄ S (MH ⁺ ): 329.1794, observed: 329.1802.

Example 37

1-(1-methylpiperidin-4-yl)porphyrin (2) :

Compound 1 (1.0g, 8.391mmol), N- methyl-4-piperidone (1.23mL, 10.069mmol) and glacial acetic acid (1.18mL, 20.978mmol) in anhydrous methanol (10mL) of solution to NaCNBH ₃ (0.63 g, 10.069 mmol) was treated at 0 °C. The resulting mixture was brought to room temperature and stirred for 3 h. The reaction was diluted with 2N NaOH solution (100 mL) and the product was extracted into _{CH 2 Cl 2 (2 × 25mL} ). The combined CH ₂ Cl ₂ layer was washed with brine (20 mL) and dried (Na ₂ SO _4). The solvent was evaporated and the crude material purified by silica gel column chromatography (2M NH ₃ in _{MeOH: CH 2 Cl 2, 3} : 97) in order to obtain a compound 2 (1.15g, 63.5%) pulp. ¹ H NMR (DMSO- d ₆ ) δ 7.06-7.01 (m, 2H), 6.59 (t, 1H, J = 6.6 Hz), 6.40 (d, 1H, J = 7.8 Hz), 3.40-3.34 (m, 3H) ), 2.97-2.91 (m, 4H), 2.30 (s, 3H), 2.09-2.00 (m, 2H), 1.80-1.72 (m, 4H); ESI-MS (m/z, %): 217 (MH) ⁺ , 42). 98(100)

5-bromo-1-(1-methylpiperidin-4-yl)porphyrin (3) :

A solution of compound 2 (1.12 g, 5.176 mmol) in EtOAc (EtOAc)EtOAc. Stirring was continued for 3 hours at the same temperature. The reaction was diluted with water (100 mL) and EtOAc (EtOAc) The combined ethyl acetate layer was washed with brine (20mL) and dried (Na ₂ SO _4). The solvent was evaporated, and the crude material purified by column chromatography to (2M NH ₃ in _{MeOH: CH 2 Cl 2, 3} : 97) to give compound 3 (1.15g, 76%) pulp. ¹ H NMR (DMSO- d ₆ ) δ 7.14-7.06 (m, 2H), 6.37 (d, 1H, J = 8.4 Hz), 3.35-3.24 (m, 3H, combined with water peak), 2.93-2.80 ( m, 4H), 2.16 (s, 3H), 2.00-1.88 (m, 2H), 1.64-1.55 (m, 4H); EI-MS (m/z, %): 293, 295 (M ⁺ , bromine isotope, 47 ), 98 (59), 97 (100), 71 (47).

1-(1-methylpiperidin-4-yl)porphyrin-5-amine (4) :

The _{Pd 2 (dba) 3 (0.077g} , 0.084mmol) in dry THF (3mL) the solution was _{PtBu 3 (1.04mL, 0.338mmol, 10} % wt in hexane) at room temperature. This mixture was treated with compound 3 (0.5 g, 1.673 mmol) in dry THF (7 mL) and then EtOAc (EtOAc EtOAc EtOAc Stir for 2 h. The reaction was taken to room temperature, quenched with 1N EtOAc (10 mL) and stirred for 10 min. This solution was basified with 1N NaOH solution (50 mL) and the product was taken to ethyl acetate (2×25mL). The combined ethyl acetate layer was washed with brine (15mL) and dried (Na ₂ SO _4). The solvent was evaporated and the crude product was purified by column chromatography on silica (2M NH ₃ in _{MeOH: CH 2 Cl 2, 2} : 98 to 5:95) to give compound 4 (0.14g, 36%) foam directly In the next step.

N-(1-(1-methylpiperidin-4-yl)porphyrin-5-yl)thiophene-2-carboxyindoleimine amide (37) :

Compound 4 (0.12g, 0.518mmol) in absolute ethanol (3mL) the solution of compound 5 (0.29g, 1.037mmol) at room temperature, and the mixture was stirred at room temperature overnight to give the (18h). The reaction was diluted with saturated NaHCO ₃ solution (20mL), and the product was extracted into _{CH 2 Cl 2 (2 × 15mL} ). The combined CH ₂ Cl ₂ layer was washed with brine (15mL) and dried (Na ₂ SO _4). The solvent was evaporated and the crude product was purified by column chromatography on silica (2M NH ₃ in _{MeOH: CH 2 Cl 2, 5} : 95) to give compound 37 (0.1g, 57%) solid. ¹ H NMR (DMSO- d ₆ ) δ 7.67 (d, 1H, J = 3.6 Hz), 7.54 (d, 1H, J = 5.1 Hz), 7.06 (t, 1H, J = 3.9 Hz), 6.61 (s, 1H), 6.51 (d, 1H, J = 8.1 Hz), 6.39 (d, 1H, J = 8.1 Hz), 6.24 (brs, 2H), 3.30-3.24 (m, 3H), 2.86-2.80 (m, 4H) ), 2.16 (s, 3H), 2.00-1.92 (m, 2H), 1.66-1.56 (m, 4H); ESI-MS (m/z, %): 341 (MH ⁺ , 100), 244 (87) ; ESI-HRMS calcd for _{C 19 H 25 N 4 S (} MH +), calcd: 341.1794; observed value: 4341.1805; HPLC purity 93.24% area.

Example 38

7-Nitro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one (1) : See Example 25 for complete experimental details and spectral data. 7-Nitro-1-(2-(piperidin-1-yl)ethyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one (2) :

Compound 1 (1.0 g, 4.85 mmol), 1-(2-chloroethyl)piperidine monohydrochloride (1.785 g, 9.70 mmol) and K ₂ CO ₃ (4.02 g, 29.10 mmol) in DMF (10 mL) The suspension was heated to 100 ° C and stirred overnight (22.5 hours). The reaction mixture was brought to room temperature and diluted with H ₂ O (100mL) and extracted with EtOAc (3 × 50mL). The combined organic layers were dried (Na ₂ SO ₄₎ and concentrated to give a brown residue. The product was isolated by column chromatography together with the 9-nitro structural isomers thereof (2N NH ₃ in _{MeOH: CH 2 Cl 2, 3} : 97) to give compound 2 (1.44g, 93.5%) brown syrup mixed . ESI-MS (m/z, %): 318.2 (MH ⁺ , 100), 233.1 (38)

7-Amino-1-(2-(piperidin-1-yl)ethyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one (3) :

A solution of compound 2 (500 mg, 1.56 mmol) in dry ethanol (10 mL) was taken eluted with Pd-C (~0.05 g) and vented with hydrogen. The reaction mixture was stirred at room temperature under a hydrogen atmosphere (balloon pressure) overnight (18 h). The mixture was filtered through a pad of celite and washed with methanol (3×25 mL). The combined organic portions were dried under reduced pressure to give crude compound 3 (0.5 g, quantitative). ¹ H-NMR (DMSO- d ₆ ) δ 1.34 (m, 6H), 1.87-2.22 (m, 10H), 5.00-5.03 (m, 2H), 6.34-6.52 (m, 2H), 6.98 (d, 1H) , J = 8.4 Hz); ESI-MS (m/z, %): 288.2 (MH ⁺ , 100), 203.1 (37)

N-(2-Sideoxy-1-(2-(piperidin-1-yl)ethyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-7-yl Thiophene-2-carboxyindoleimine (38) :

The compound in absolute ethanol (10 mL) solution of 3 (449mg, 1.64mmol), compound 4 (0.936g, 3.28mmol) and treated at room temperature with stirring overnight (16h). The reaction mixture was diluted with saturated NaHCO ₃ solution (50mL), and extracted with _{CH 2 Cl 2 (2 × 50mL} ). The combined organic portions were washed with brine (50mL), dried (Na ₂ SO ₄₎ and concentrated. The crude product was purified by column chromatography to (2N NH ₃ in _{MeOH: CH 2 Cl 2, 2} : 98, then 4:96) to give Compound 38 (410.3mg, 66.2%) as a yellow solid. ¹ H-NMR (DMSO- d ₆ ) δ 1.35 (m, 6H), 2.01-2.30 (m, 10H), 2.72 (brs, 2H), 6.44 (brs, 2H), 6.75 (m, 2H), 7.10 ( m, 1H), 7.28 (d, 1H, J = 8.3 Hz), 7.62 (d, 1H, J = 5.1 Hz), 7.74 (d, 1H, J = 3.4 Hz). ESI-MS (m/z, %): 397.2 (MH ⁺ , 78), 312 (28), 156 (100), 148 (53); ESI-HRMS calculated for C ₂₂ H ₂₉ N ₄ OS (MH ⁺ ), calculated: 397.2070; observed: 397.2056; HPLC purity: 93.90% area.

Example 39

4,5-Dihydro-1H-benzo[b]azepine-2(3H)-one (1) : See Example 25 for complete experimental details and spectral data 2,3,4,5-tetrahydro-1H-benzo[b]azepine (2) :

The LiAlH ₄ (49.63mL, 49.63mmol) and suspended in 1.0M THF solution was added dropwise to the solution was treated in THF (60mL) Compound 1 (2.0g, 12.41mmol), while stirring at 0 ℃. The resulting reaction mixture was brought to room temperature and stirred for 23 hours. The reaction _{H 2 O (1.9mL), 1N} NaOH solution (1.9 mL), and H ₂ O (1.9mL) quenching, while a white precipitate formed. The suspension was filtered, and the precipitate was washed with _{CH 2 Cl 2 (3 × 50mL} ). The filtrate was dried (Na ₂ SO _4), concentrated, and dried under reduced pressure to give compound 2 (1.55g, 84.7%) as a brown solid. ¹ H-NMR (DMSO- d ₆ ) δ 1.53 (m, 2H), 1.64 (m, 2H), 2.63 (m, 2H), 2.88 (m, 2H), 5.15 (brs, 1H), 6.66 (td, 1H, J = 7.5, 1.2 Hz), 6.78 (dd, 1H, J = 7.4, 1.0 Hz), 6.93 (t, 1H, J = 7.4 Hz), 7.00 (d, 1H, J = 7.0 Hz); EI- MS (m/z, %): 147 (M ⁺ , 100), 146 (44), 132 (42), 119 (40), 118 (89)

1-(1-Methylpiperidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine (3) :

Compound 2 (1.0g, 6.79mmol), N- methyl-4-piperidone (1.00mL, 8.15mmol) and acetic acid (0.96mL, 16.98mmol) (10mL) of solution in anhydrous methanol to NaCNBH ₃ ( 0.51 g, 8.15 mmol) was treated at 0 °C. The reaction mixture was brought to room temperature and stirred overnight (15 hours). And the reaction was extracted with 2N NaOH (100mL) quenching _{CH 2 Cl 2 (2 × 25mL} ). The combined organic portions were washed with brine (30mL), dried (Na ₂ SO ₄₎ and concentrated. The crude product was purified by column chromatography (2.0N NH ₃ in _{MeOH: CH 2 Cl 2, 3} : 97) in order to obtain a compound 3 (0.82g, 49.4%) as a yellow oil. ¹ H-NMR (DMSO- d ₆ ) δ 1.55 (m, 4H), 1.74 (m, 4H), 1.96 (td, 2H, J = 11.3, 2.6 Hz), 2.15 (s, 3H), 2.66 (m, 2H), 2.78 (m, 2H), 2.93 (m, 2H), 3.17 (m, 1H), 6.74 (t, 1H, J = 7.3 Hz), 6.90 (d, 1H, J = 8.2 Hz), 7.01 ( m, 2H); EI-MS (m/z, %): 244 (M ⁺ , 24), 97 (100), 71 (37)

7-Bromo-1-(1-methylpiperidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine (4) :

A solution of compound 3 (0.73 g, 2.29 mmol) in EtOAc (EtOAc) The reaction mixture was stirred at 0 &lt;0&gt;C for 2 h and kept at 0 °C overnight. The reaction mixture was diluted with water (100 mL) andEtOAc. The combined organic layers were washed with brine (25mL), dried (Na ₂ SO ₄₎ and concentrated. The product was filtered through a short silica gel plug (2.0N NH ₃ in _{MeOH: CH 2 Cl 2, 2.5} : 97.5) to give Compound 4 (0.915g, 95.3%) as a yellow oil. ¹ H-NMR (DMSO- d ₆ ) δ 1.56 (m, 4H), 1.72 (m, 4H), 1.96 (td, 2H, J = 10.9, 2.2 Hz), 2.15 (s, 3H), 2.65 (m, 2H), 2.76 (m, 2H), 2.93 (m, 2H), 3.14 (m, 1H), 6.83 (d, 1H, J = 8.5 Hz), 7.19 (td, 2H, J = 8.6, 2.4 Hz); EI-MS (m/z, %) 324 (M ⁺ , 14) 322 (M ⁺ , 14), 98 (25), 97 (100), 96 (25), 71 (38)

1-(1-Methylpiperidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-7-amine (5) :

The _{Pd 2 (dba) 3 (70mg} , 0.077mmol) and PtBu ₃ 10% wt in hexanes (0.94mL, 0.31mmol) in THF (5.0mL) suspension of, compound 4 (500.0mg, 1.55mmol) in This was treated with THF (5.0 mL) EtOAc (EtOAc) The resulting brown mixture was stirred at 100 &lt;0&gt;C for 2 h then cooled to rt and EtOAc &lt And this mixture was extracted with 1N NaOH (25mL) and basified to _{CH 2 Cl 2 (2 × 100mL} ). The combined organic portions were washed with brine (100mL), dried (Na ₂ SO ₄₎ and concentrated to give a dark brown residue. The crude product was purified by flash chromatography on silica _{(MeOH: CH 2 Cl 2,} 5:95, and then to 2N NH ₃ in _{MeOH: CH 2 Cl 2, 5} : 95) to give compound 5 (339.6mg, 84.7% ) Dark viscous oil.

N-(1-(1-methylpiperidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-yl)thiophene-2-carboxyindole Amine amide (39) :

Compound 8 (321.6mg, 1.24mmol) in absolute ethanol (10 mL) of the solution, compound 6 (707mg, 2.48mmol) treated at rt. The reaction mixture was stirred at room temperature for 16 hours, then diluted with saturated NaHCO ₃ solution (50mL) and extracted in CH ₂ Cl ₂ (2 × 50mL). The combined organic portions were washed with brine (50mL), dried (Na ₂ SO ₄₎ and concentrated to give a brown residue. The crude product was purified by column chromatography on silica _{(MeOH: CH 2 Cl 2,} 2:98, followed by 2N NH ₃ in _{MeOH: CH 2 Cl 2, 4} : 96 to5: 95) to give compound 39 (374.6mg, 81.9%) yellow residue. ¹ H-NMR (DMSO- d ₆ ) δ 1.56-1.79 (m, 9H), 1.97 (t, 2H, J = 10.5 Hz), 2.16 (s, 3H), 2.65 (brs, 2H), 2.80 (d, 2H, J = 10.2 Hz), 2.91 (brs, 2H), 3.12 (m, 1H), 6.30 (brs, 2H), 6.59 (m, 2H), 6.89 (d, 1H, J = 8.9 Hz), 7.07 ( t, 1H, J = 4.5 Hz), 7.57 (d, 1H, J = 5.1), 7.70 (d, 1H, J = 3.5 Hz); ESI-MS (m/z, %) 369 (MH ⁺ , 35) , 272 (100). ESI-HRMS calcd for _{C 21 H 29 N 4 S (} MH +), calcd: 369.2101; observations: 369.2107; HPLC purity: 97.31% area.

Example 40

7-Amino-1-(2-(piperidin-1-yl)ethyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one (1) : See Example 38 has complete experimental details and spectral data 1-(2-(piperidin-1-yl)ethyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine -7-amine (2) :

The LiAlH ₄ (1.0M in THF, 3.2mL, 3.20mmol) of the suspension, a solution of compound 1 (230.7mg, 0.803mmol) (6mL ) was treated at 0 ℃ of anhydrous THF. The reaction was brought to room temperature and stirred overnight (for 16 h), then _{H 2 O (0.1mL), 1N} NaOH (0.1mL) quenched, then, if H ₂ O (0.1mL) was heated, a white precipitate formed. The precipitate was filtered off and washed with _{CH 2 Cl 2 (3 × 25mL} ). The combined organic portion was concentrated and purified by column chromatography on silica (2N NH ₃ in _{MeOH: CH 2 Cl 2, 5:95} ) to give compound 2 (197.7mg, 90.0%) of brown residue. ¹ H-NMR (DMSO- d ₆ ) δ 1.36 (m, 2H), 1.45 (m, 6H), 1.60 (m, 2H), 2.36 (m, 6H), 2.73 (m, 2H), 3.06 (t, 2H, J=7.3Hz), 3.33(s,3H), 4.55(brs,2H),6.31(m,2H),6.64(d,1H,J=8.1Hz);ESI-MS(m/z,% ): 274 (MH ⁺ , 100)

N-(1-(2-(piperidin-1-yl)ethyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-yl)thiophene-2-carboxylate醯imine amide (40) :

Compound 2 (180mg, 0.659mmol) in ethanol (10 mL) at room temperature, the solution to 3 (0.376g, 1.32mmol) process. The reaction mixture was stirred at room temperature overnight (16h), and then diluted with saturated NaHCO ₃ solution (50mL), and extracted into _{CH 2 Cl 2 (2 × 50mL} ). The combined organic portions were washed with brine (50mL), dried (Na ₂ SO ₄₎ and concentrated. The crude product was purified by column chromatography on silica (2N NH ₃ in _{MeOH: CH 2 Cl 2, 2.5} : 97.5) to give Compound 40 (209mg, 83.3%) as an orange solid. ¹ H-NMR (DMSO- d ₆ ) δ 1.37 (m, 2H), 1.48 (m, 6H), 1.65 (m, 2H), 2.42 (m, 6H), 2.65 (m, 2H), 2.85 (m, 2H), 3.18 (m, 2H), 6.31 (brs, 2H), 6.62 (m, 2H), 6.88 (d, 1H, J = 9.0 Hz), 7.08 (t, 1H, J = 4.3 Hz), 7.57 ( d, 1H, J = 5.05 Hz), 7.70 (d, 1H, J = 3.5 Hz); ESI-MS (m/z, %): 383 (MH ⁺ , 100), 272 (85), 252 (51) , 192 (91); ESI- HRMS calcd for _{C 22 H 31 N 4 S (} MH +), calcd: 383.2279; observations: 383.2263; HPLC purity: 97.02% area.

Example 41

3-chloro-N-(2-fluorophenyl)propanamide (3)

2-Fluoroaniline (2 g, 17.99 mmol) was dissolved in acetone (30 mL) and pyridine (2.91 mL, 35.99 mmol). To this solution was slowly added 3-chloropropionyl chloride (3.42 g, 26.99 mmol). The reaction mixture began to reflux and when the mixture had cooled to room temperature (~30 min), TLC analysis indicated that the reaction was completed. The reaction mixture was diluted with water and EtOAc _(aq) (1 N) andEtOAc. The combined organic extracts were dried with sodium s Yield: 3.5 g, 97%. ¹ H NMR (CDCl ₃ ) δ 2.87 (t, 2H, J = 6.7 Hz), 3.89 (t, 2H, J = 6.7 Hz), 7.10 (m, 3H), 7.52 (brs) , 1H), 8.30 (t, 1H, J = 7.5 Hz). EI-MS (m/z, %): 201.1 (M+, 22), 111.1 (100)

8-fluoro-3,4-dihydroquinolin-2(1H)-one (4)

3-Chloro-N-(2-fluorophenyl)propanamide (3.3 g, 16.4 mmol) and aluminum trichloride (10.9 g, 81.8 mmol) were combined in a RB flask with a stir bar and Ventilation by argon. This mixture of 2 solids was heated to 160 ° C to form a melt which was stirred for 1.5 h. This mixture was removed from the heating bath and, when cooled to below 100 ° C, water was carefully added to quench. The resulting mixture was cooled to room temperature, neutralized with NaOH and extracted with dichloromethane (3×). The combined organics were dried, filtered and evaporated elut elut elut elut 1H NMR showed some impurities. Yield: 2.35 g, 88%. ¹ H NMR (CDCl ₃ ) δ 2.66 (t, 2H, J = 7.6 Hz), 3.01 (t, 2H, J = 7.6 Hz), 6.96 (m, 3H), 8.11 (brs) , 1H)

1-(2-(Dimethylamino)ethyl)-8-fluoro-3,4-dihydroquinolin-2(1H)-one (6)

8-Fluoro-3,4-dihydroquinolin-2(1H)-one (2.31 g, 13.98 mmol), 2-chloro-N,N-dimethylethylamine hydrogen chloride (4.03 g, 27.9 mmol) and Potassium carbonate (11.78 g, 85.3 mmol) was combined in a round bottom flask containing a stir bar. The flask was vented with argon and DMF was added. The white suspension was stirred at room temperature overnight. The mixture was diluted with ethyl acetate and washed with water (5x) and brine. The organic phase was dried, filtered and concentrated and purified eluting elut Yield: 2.86 g, 86%. ¹ H NMR (CDCl ₃ ) δ 2.24, (s, 6H), 2.51 (t, 2H, J = 7.0 Hz), 2.59 (t, 2H, J = 7.0 Hz), 2.87 ( t, 2H, J = 7.0 Hz), 4.09 (t, 2H, J = 7.0 Hz), 6.98 (m, 3H). ESI-MS: 237 (MH+, 29), 192 (100)

1-(2-(Dimethylamino)ethyl)-8-fluoro-6-nitro-3,4-dihydroquinolin-2(1H)-one (7)

1-(2-(Dimethylamino)ethyl)-8-fluoro-3,4-dihydroquinolin-2(1H)-one (2.86 g, 12.11 mmol) was weighed to a round bottom flask. The flask was equipped with a stir bar. Concentrated sulfuric acid (30 mL) was added thereto, and the flask was cooled to -5 ° C in an ice/salt bath. To the solution was stirred, nitric acid (90%, 615.5 μL, 13.2 mmol) was added, and the mixture obtained was stirred for 30 minutes. The reaction mixture was quenched with ice and NaOH _(aq) . The product was extracted with CH ₂ Cl ₂ (3x). The combined organic phase was dried, filtered and concentrated and chromatographed on silica using 0-10% (2M NH ₃ in MeOH) in dichloromethane to give the product look. Yield: 1.1 g, 32%, the product still has some impurities). ¹ H NMR (CDCl ₃ ) δ 2.20 (s, 6H), 2.48 (t, 2H, J = 7.0 Hz), 2.67 (t, 2H, J = 7.0 Hz), 2.98 (t, 2H, J = 7.0 Hz) , 4.16 (t, 2H, J = 7.0 Hz), 7.89 (m, 2H). ESI-MS: 282 (MH+, 100), 237 (50), 192 (27)

6-Amino-1-(2-(dimethylamino)ethyl)-8-fluoro-3,4-dihydroquinolin-2(1H)-one (8)

1-(2-(Dimethylamino)ethyl)-8-fluoro-6-nitro-3,4-dihydroquinolin-2(1H)-one (500 mg, 1.77 mmol) was weighed to A round bottom flask equipped with a stir bar. Ethanol (10 mL) and THF (2 mL) were added followed by Pd over 10 wt.% activated carbon. The flask was fitted with a hydrogen balloon, vented and refilled with hydrogen. The black suspension was stirred at room temperature for 3 h. The solid palladium was filtered off through a mash of algae, and the diatomaceous earth pad was washed with methanol. The filtrate was concentrated and chromatographed on silica using 0-10% (2M NH ₃ in MeOH) in ethyl acetate to give the product. Yield: 325 mg, 72%. EI-MS: 251 (M+, 3), 58 (100)

N-(1-(2-(Dimethylamino)ethyl)-8-fluoro-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2- Carboxylimine amide (41)

6-Amino-1-(2-(dimethylamino)ethyl)-8-fluoro-3,4-dihydroquinolin-2(1H)-one (312 mg, 1.24 mmol) was stirred to dissolve In ethanol (15 mL). To this solution was added methylthiophene-2-carboquinone thiocarboxylate hydrogen iodide (708 mg, 2.48 mmol). The resulting suspension was stirred at room temperature for 2 days. When TLC analysis indicated the reaction was completed, the mixture was diluted with water and aqueous sodium carbonate and then extracted with dichloromethane (3x). The combined organic phase was dried, filtered and concentrated and the crude product was chromatographed on silica using 0-10% (2M NH ₃ in MeOH) in ethyl acetate, and then the second time, using 20-80% MeCN in carbonate The aqueous solution of ammonium and ammonium hydroxide buffer was adjusted to pH 10.6. Yield: 27 mg. ¹ H NMR (DMSO-d ₆ ) δ 2.14 (s, 6H), 2.44 (t, 2H, J = 6.7 Hz), 2.49 (m, 2H, covered by DMSO peak), 2.80 (t, 2H, J) = 6.6 Hz), 3.95 (t, 2H, J = 6.5 Hz), 6.61 (m, 4H), 7.09 (m, 1H), 7.62 (m, 1H), 7.75 (m, 1H). ESI-MS: 361 (MH+, 100), 316 (40), 158.6 (57), 136 (37).

Example 42

1-(2-(Dimethylamino)ethyl)-8-fluoro-6-nitro-3,4-dihydroquinolin-2(1H)-one (1)

For complete experimental details and spectral data, see Example 41

2-(8-Fluoro-6-nitro-3,4-dihydroquinolin-1(2H)-yl)-N,N-dimethylethylamine (2)

Add 1-(2-(dimethylamino)ethyl)-8-fluoro-6-nitro-3,4-dihydroquinolin-2(1H)-one (600 mg, 2.13 mmol) to the preparation A round bottom flask with a stir bar. The flask was sealed and vented with argon. Borane THF (1 M solution in THF, 21.3 mL, 21.3 mmol) was added to the starting material and stirred to dissolve. The reaction mixture was heated to reflux overnight. The reaction was cooled to 0.degree. C. and quenched with methanol (20 mL). The mixture was concentrated in vacuo, taken up in MeOH then EtOAc. The mixture was concentrated onto silica gel, and chromatographed using 0-10% (2M NH ₃ in MeOH) in dichloromethane. Yield: 364 mg, 64%. ¹ H NMR (CDCl ₃ ) δ 1.95 (m, 2H), 2.27 (s, 6H), 2.56 (m, 2H), 2.77 (m, 2H), 3.41 (m, 4H), 7.69 (m, 1H), 7.77 (dd, 1H, J = 9 Hz, 2.7 Hz). EI-MS: 58 (100)

1-(2-(Dimethylamino)ethyl)-8-fluoro-1,2,3,4-tetrahydroquinolin-6-amine (3)

2-(8-Fluoro-6-nitro-3,4-dihydroquinolin-1(2H)-yl)-N,N-dimethylethylamine (340 mg, 1.27 mmol) was weighed to a round bottom flask The flask was equipped with a stir bar. Ethanol (8 mL) was added followed by Pd (10 wt.% on activated carbon). The flask was fitted with a hydrogen balloon, the air was vented, and hydrogen was refilled. The reaction mixture was subjected to balloon pressure. at room temperature stirred for 2h. the reaction mixture was filtered through a pad of diatomaceous earth, the pad was washed with methanol. the filtrate was concentrated and chromatographed on silica using 0-10% (2M NH ₃ in MeOH) in dichloromethane Yield: 270 mg, 89%. ESI-MS: 238 (MH+, 100), 193 (37), 147 (31)

N-(1-(2-(Dimethylamino)ethyl)-8-fluoro-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboxyindoleimine (42)

Stirring 1-(2-(dimethylamino)ethyl)-8-fluoro-1,2,3,4-tetrahydroquinolin-6-amine (222 mg, 0.935 mmol) in a round bottom flask In ethanol. To this solution was added methylthiophene-2-carboquinone thiocarboxylate hydrogen iodide (533 mg, 1.87 mmol). The resulting suspension was stirred at room temperature overnight. When the reaction was completed by TLC, the mixture was diluted with water and aqueous sodium carbonate, and then extracted with dichloromethane (3x). The combined organic phase was dried, filtered and concentrated and the crude product was chromatographed on silica using 0-10% (2M NH ₃ in MeOH) in ethyl acetate, and then the second time, using 20-80% MeCN in carbonate The aqueous solution of ammonium and ammonium hydroxide buffer was adjusted to pH 10.6. Yield: 46 mg, 15%. ¹ H NMR (DMSO-d ₆ ) δ 1.75 (m, 2H), 2.16 (s, 6H), 2.46 (m, 2H), 2.66 (m, 2H), 3.12 (m, 4H) ), 6.40 (m, 4H), 7.07 (m, 1H), 7.57 (m, 1H), 7.71 (m, 1H). ESI-MS: 347 (MH+, 33), 276 (100), 143 (12)

Example 43

3-(5-Nitro-2-oxo oxalin-3-ylidene)pyrrolidine-1-carboxylic acid tert-butyl ester (2):

Compound 1 (1.0g, 5.613mmol), N -Boc-3- pyrrolidone (1.039mL, 5.613mmol) in 7N NH ₃ in methanol (10mL) of solution was refluxed for 2h. The reaction was brought to room temperature, filtered, washed with methanol (2 × 5mL) and dried in vacuo to give a solid compound 2 (1.88g, 97%). ¹ H NMR (DMSO- d ₆ ) δ 11.29 (s, 1H), 8.19 (dd, 1H, J = 2.1, 8.7 Hz), 8.14 (d, 1H, J = 1.8 Hz), 7.05 (d, 1H, J) = 8.4 Hz), 4.56 (s, 2H), 3.61 (t, 2H, J = 7.2 Hz), 3.36-3.30 (m, 2H, confluent in the DMSO peak), 1.44 (s, 9H); ESI-MS ( m/z,%): 368 (M+Na, 23), 272 (48), 246 (MH ⁺ -Boc, 100)

3-(5-Amino-2-p-oxyporphyrin-3-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (3):

Compound 2 (0.3g, 0.868mmol) in a solution of 7N NH ₃ in methanol (10mL), the order Pd-C (~ 0.03g) process, hydrogen gas and ventilation. The reaction was stirred at room temperature under a hydrogen atmosphere (balloon pressure) for 3 h. The reaction was filtered through a pad of celite and washed with methanol (3×10 mL). The combined organic layers were evaporated and the crude product was purified by column chromatography to (2M NH ₃ in _{MeOH: CH 2 Cl 2, 5} : 95) to give compound 3 (0.25g, 91%) solid. ¹ H NMR (DMSO- d ₆ ) δ 9.99 (s, 1H), 6.57-6.50 (m, 2H), 6.39 (d, 1H, J = 8.7 Hz), 4.69 (d, 2H, J = 4.2 Hz), 3.56-3.35 (m, 3H), 3.15-3.04 (m, 2H), 2.50-2.49 (m, 1H), 1.98-1.66 (m, 2H), 1.37 (s, 9H); ESI-MS (m/z) ,%): 340 (M+Na, 5), 244 (100), 218 (MH ⁺ -Boc, 84)

3-(2-Sideoxy-5-(thiophene-2-carboxyindolinamine) porphyrin-3-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (5):

Compound 3 (0.24g, 0.756mmol) in absolute ethanol (5mL) of a solution, compound 4 (0.43g, 1.512mmol) at room temperature, and the mixture thus obtained and it was stirred for 16h. The reaction was diluted with saturated NaHCO ₃ solution (25mL) and the product was extracted into _{CH 2 Cl 2 (2 × 20mL} ). The combined organic layers were dried (Na ₂ SO _4), the solvent was evaporated and the crude product was purified by column chromatography to (2M NH ₃ in _{MeOH: CH 2 Cl 2, 3} : 97) to give compound 5 (0.225g, 70%) solid. ¹ H NMR (DMSO- d ₆ ) δ 10.29 (s, 1H), 7.71 (d, 1H, J = 2.4 Hz), 7.58 (d, 1H, J = 5.1 Hz), 7.08 (t, 1H, J = 4.5) Hz), 6.78-6.76 (m, 2H), 6.68 (d, 1H, J = 7.8 Hz), 6.39 (s, 2H), 3.59-3.25 (m, 3H), 3.21-3.05 (m, 2H), 2.56 - 2.50 (m, 1H), 2.03-1.68 (m, 2H), 1.37 (s, 9H); ESI-MS (m/z, %): 427 (MH ⁺ , 100).

N-(2-Sideoxy-3-(pyrrolidin-3-yl)porphyrin-5-yl)thiophene-2-carboxyindoleimine amide (43) :

A solution of compound 5 (0.21 g, 0.492 mmol) in MeOH (10 mL) The reaction was brought to room temperature and the solvent was evaporated. This crude material was dissolved in water (10 mL), filtered and washed with water. The combined aqueous layers were evaporated to give compound 43 (0.173 g, 88%). ¹ H NMR (DMSO- d ₆ ) δ 11.50 (brs, 1H), 10.87 (d, 1H, J = 3.0 Hz), 9.79 (s, 1H), 9.69-9.46 (m, 2H), 8.80 (d, 1H) , J=7.5Hz), 8.19-8.16(m, 2H), 7.43(s,1H), 7.37(t,1H,J=4.5Hz), 7.30(d,1H,J=8.1Hz),7.01(d , 1H, J=8.1Hz), 3.50-3.32 (m, 1H), 3.30-3.02 (m, 3H), 2.75-2.50 (m, 2H), 2.18-2.08 (m, 1H), 1.96-1.40 (m , 1H); HPLC purity 95.52% area.

Example 44

N, N- dimethyl-2- (7-nitro-3,4-dihydro-quinoline -1 (2H) - yl) ethylamine (1): See Example 32 Real complete experimental details and spectral data Methyl (2-(7-nitro-3,4-dihydroquinolin-1(2H)-yl)ethyl)aminecarboxylic acid phenyl ester (2) :

Compound 1 (1.5g, 6.016mmol) in dry CH ₂ Cl ₂ (25mL) of solution to phenyl chloroformate (1.13mL, 9.024mmol) at room temperature, and the resulting mixture was stirred for the thus obtained 24h. The reaction was extracted into _{CH 2 Cl 2 (2 × 50mL} ) was diluted (50mL) and the product of 1N NaOH solution. The combined organic layers were washed with brine (15mL) and dried (Na ₂ SO _4). The solvent was evaporated and the crude product was purified by column chromatography on silica (CH ₂ Cl ₂₎ to give compound 2 (1.89g, 89%) pulp. ¹ H NMR (CDCl ₃ ) δ 7.49-7.31 (m, 4H), 7.18 (t, 1H, J = 7.2 Hz), 7.04-6.90 (m, 3H), 3.68-3.55 (m, 4H), 3.41 (t) , 2H, J = 5.7 Hz), 3.16-3.07 (m, 3H), 2.79 (t, 2H, J = 6.3 Hz), 1.99-1.91 (m, 2H); ESI-MS (m/z, %): 378 (M+Na, 29), 356 (MH ⁺ , 100)

Phenyl 2-(7-amino-3,4-dihydroquinolin-1(2H)-yl)ethyl(methyl)aminecarboxylate (3) :

A solution of compound 2 (1.85 g, 5.205 mmol) in dry ethanol (30 mL) was taken eluting with Pd-C (~0.2 g) and vented with hydrogen. The reaction was stirred at room temperature under hydrogen (balloon pressure) for 3 h. The reaction was filtered through a pad of celite and washed with methanol (3×20 mL). The combined organic layers were evaporated to give a crude compound 3 (1.67 g, 99%). ESI-MS (m/z, %): 326 (MH ⁺ , 100).

Methyl (2-(7-(thiophene-2-carboxyindolinamine)-3,4-dihydroquinolin-1(2H)-yl)ethyl)amine)carboxylate (5) :

Compound 3 (1.65g, 5.070mmol) in absolute ethanol (50mL) of solution of compound 4 (2.89g, 10.141mmol) at room temperature, and the mixture thus obtained and it was stirred for 24h. The reaction was diluted with saturated NaHCO ₃ solution (100mL), and the product was extracted into _{CH 2 Cl 2 (2 × 50mL} ). The combined organic layers were washed with brine (25mL) and dried (Na ₂ SO _4). The solvent was evaporated, and the crude product was purified by column chromatography on silica (2M NH ₃ in _{MeOH: CH 2 Cl 2, 2.5} : 97.5) to give Compound 5 (1.8g, 82%) foam. ¹ H NMR (DMSO- d ₆ ) δ 7.53-7.51 (m, 1H), 7.42-7.37 (m, 1H), 7.31-7.27 (m, 1H), 7.23-7.16 (m, 1H), 7.13-7.02 ( m, 3H), 6.96 (d, 1H, J = 7.5 Hz), 6.91 (d, 1H, J = 7.8 Hz), 6.29 (d, 1H, J = 4.5 Hz), 6.22 (d, 1H, J = 7.8) Hz), 5.71 (brs, 1H), 4.78 (brs, 1H), 3.65-3.52 (m, 4H), 3.35 (t, 2H, J = 5.7 Hz), 3.11, 3.03 (2s, 3H), 2.74 - 2.69 (m, 2H), 1.97-1.89 (m, 2H); ESI-MS (m/z, %): 435 (MH ⁺ , 100)

N-(1-(2-(methylamino)ethyl)-1,2,3,4-tetrahydroquinolin-7-yl)thiophene-2-carboximine amide (44) :

Compound 5 (1.30g, 2.991mmol) in _{ethanol: H 2 O (30mL, 3} : 1) of solution to NaOH (1.19g, 29.916mmol) at room temperature process, and the resulting solution was refluxed for 6h. The reaction was brought to room temperature, diluted with CH ₂ Cl ₂ (25 mL), and washed with brine (15mL). The aqueous layer was re-extracted with _{CH 2 Cl 2 (2 × 20mL} ), and the combined CH ₂ Cl ₂ layer was dried (Na ₂ SO _4). The solvent was evaporated, and the crude product was purified by column chromatography on silica (2M NH ₃ in _{MeOH: 9 CH 2 Cl 2,} 5:: 95 to 1) to give a solid compound 44 (0.6g, 64%). ¹ H NMR (DMSO- d ₆ ) δ 7.69 (d, 1H, J = 3.0 Hz), 7.57 (dd, 1H, J = 0.9, 5.1 Hz), 7.07 (dd, 1H, J = 3.6, 5.1 Hz), 6.78 (d, 1H, J = 7.5 Hz), 6.22 (brs, 2H), 6.08 (d, 1H, J = 1.2 Hz), 5.99 (dd, 1H, J = 1.5, 7.6 Hz), 3.27-3.23 (m , 4H), 2.68-2.61 (m, 4H), 2.31 (s, 3H), 1.87-1.80 (m, 2H); ESI-MS (m/z, %): 315 (MH ⁺ , 100); HRMS calcd for _{C 17 H 23 N 4 S (} MH +), calcd: 315.1637; observations: 315.1652; HPLC purity 98.67% area.

Example 45

7-Nitro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one (1) : With complete experimental details and spectral data with reference to the above experimental examples 1-(2-(1-methylpyrrolidin-2-yl)ethyl)-7-nitro-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one ( 2) :

Compound 1 (1.50 g, 7.27 mmol), chloroethyl-1-methylpyrroleidine hydrogen chloride (2.68 g, 14.55 mmol), NaI (0.545 g, 3.64 mmol) and K ₂ CO ₃ (6.03 g, 43.65 mmol) A suspension of anhydrous DMF (30 mL) was stirred at room temperature overnight (18 h). The reaction mixture was diluted with water (2OmL) The combined organic portions were washed with brine (50mL), dried (Na ₂ SO ₄₎ and concentrated. The product was isolated by column chromatography together with the 9-nitro structural isomers thereof (2.0N NH ₃ in _{MeOH: CH 2 Cl 2, 3} : 97) to give 2 (1.54g, 66%) a brown syrup mixed . ESI-MS (m/z, %): 318 (MH ⁺ , 100)

7-Amino-1-(2-(1-methylpyrrolidin-2-yl)ethyl)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-one ( 3):

A solution of 2 (600 mg, 1.89 mmol) in dry ethanol (10 mL) was taken eluted with Pd-C (~0.06 g). The reaction mixture was stirred at room temperature under a hydrogen atmosphere (balloon pressure) overnight (18 h). The mixture was filtered through a pad of celite and washed with methanol (3×25 mL). The combined organic fractions were concentrated to give a brown residue. The product was purified by dry column chromatography (2N NH ₃ in _{MeOH: CH 2 Cl 2, 5} : 95) in order to obtain a compound 3 (435mg, 80%) as a colorless foam. ¹ H-NMR (DMSO- d ₆ , 300 MHz) δ: 1.29-1.38 (m, 2H), 1.54-1.60 (m, 2H), 1.66-1.82 (m, 2H), 1.89-2.10 (m, 10H), 2.38-2.45 (m, 2H), 2.84-2.91 (m, 1H), 5.07 (brs, 2H), 6.36-6.52 (m, 2H), 6.85-6.98 (m, 1H)

1-(2-(1-Methylpyrrolidin-2-yl)ethyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-7-amine (4):

Compound 3 (825mg, 2.87mmol) in dry THF (15mL) of solution was cooled to 0 ℃, and added dropwise LiAlH ₄ (1.0M in THF, 11.5mL, 11.5mmol) process. The reaction mixture was warmed to room temperature and stirred overnight (23 h). The reaction mixture was cooled to 0 ℃ and to _{H 2 O (0.4mL), 2N} NaOH (0.4mL) quenching, and additional H ₂ O (0.4mL) and stirred for 30 minutes at which time a white precipitate formed. The solid was filtered off, and is washed with CH ₂ Cl ₂ (2 × 50mL), the filtrate was concentrated. The crude product was purified by column chromatography (2N NH ₃ in _{MeOH: CH 2 Cl 2, 5} : 95) in order to obtain a compound 4 (590mg, 75%) mixed with a brown syrup.

N-(1-(2-(1-methylpyrrolidin-2-yl)ethyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-7-yl)thiophene -2-Carboxylimine amide (45):

The 4 (170mg, 0.62mmol) in absolute ethanol (15mL) was treated in the 5 (0.355g, 1.24mmol) and stirred at room temperature overnight (17h). The reaction mixture was diluted with saturated NaHCO ₃ solution (100 mL) and in _{CH 2 Cl 2 (2 × 50mL} ) and extracted. The combined organic portions were washed with brine (50mL), dried (Na ₂ SO ₄₎ and concentrated. The crude product was purified by dry column chromatography to _{(MeOH: CH 2 Cl 2,} 2: 98, then to 2N NH ₃ in MeOH: CH ₂ Cl ₂ 3:97) to give Compound 45 (177mg, 74%) as a yellow solid . ¹ H-NMR (DMSO- d ₆ ) δ: 1.38-1.69 (m, 8H), 1.83-1.89 (m, 2H), 2.02-2.12 (m, 2H), 2.19 (s, 3H), 2.65-2.68 ( m, 2H), 2.80-3.12 (m, 5H), 6.32 (brs, 2H), 6.62-6.64 (m, 2H), 6.85-6.88 (d, 1H, J = 8.9 Hz), 7.06-7.09 (t, 1H, J = 3.8 Hz), 7.56-7.58 (d, 1H, J = 5.0 Hz), 7.69-7.71 (d, 1H, J = 3.6 Hz); ESI-MS (m/z, %): 383 (MH) ⁺ , 33), 192 (100), 142 (51). ESI-HRMS calcd for _{C 22 H 30 N 4 S (} MH +), calcd: 383.2253; observations: 383.2263; HPLC purity: 93.49% area.

Example 46

2,3,4,5-tetrahydro-1H-benzo[b]azepine (1): See Example 39 for complete experimental details and spectral data. 3-(2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (2):

Cooling solution of compound 1 (1.74 g, 11.82 mmol), N-Boc-3-pyrrolidone (3.28 g, 17.73 mmol) and acetic acid (1.35 mL, 20.68 mmol) in anhydrous methanol (25 mL) was treated at NaCNBH ₃ (1.67g, 26.59mmol) in methanol (5mL) of. The reaction was brought to room temperature and stirred overnight (16 h). The reaction was diluted with 2N EtOAc (EtOAc) (EtOAc) The combined organic portions were washed with brine (50mL), dried (Na ₂ SO ₄₎ and concentrated. The crude product was purified by column chromatography to (EtOAc in: hexanes, 1: 4) to give compound 2 (3.24g, 87%) pulp. ¹ H NMR (DMSO- d ₆ ) δ 1.35-1.39 (m, 9H), 1.44-1.64 (m, 4H), 1.81-1.88 (m, 1H), 2.13-2.18 (m, 1H), 2.67-2. m, 4H), 3.04-3.07 (m, 1H), 3.16-3.22 (m, 1H), 3.38-3.44 (m, 1H), 3.53-3.60 (m, 1H), 4.01-4.04 (m, 1H), 6.83-6.87 (m, 1H), 6.98-7.00 (m, 1H), 7.08-7.13 (m, 2H); ESI-MS (m/z, %): 317 (MH ⁺ , 7), 261 (100)

3-(7-Bromo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (3):

A solution of compound 2 (3.15 g, 9.97 mmol) in EtOAc (EtOAc)EtOAc. The reaction mixture was stirred at 0&lt;0&gt;C for 3 h then diluted with water (100 mL) The combined organic portions were washed with brine (100mL), dried (Na ₂ SO ₄₎ and concentrated. The crude product was purified by column chromatography to (EtOAc in: hexanes, 1: 9) to give compound 3 (3.26g, 83%) foam. ¹ H NMR (DMSO- d ₆ ) δ 1.38 (s, 9H), 1.41-1.52 (m, 5H), 1.80-1.87 (m, 1H), 2.12-2.17 (m, 1H), 2.65-2.69 (m, 2H), 2.79-2.92 (m, 2H), 3.00-3.08 (m, 1H), 3.15-3.25 (m, 1H), 3.53-3.59 (m, 1H), 3.96-4.04 (m, 1H), 6.93 6.96 (d, 1H, J = 8.4 Hz), 7.23 (dd, 1H, J = 2.4, 8.4 Hz), 7.29 (d, 1H, J = 2.4 Hz); ESI-MS (m/z, %): 395 (MH ⁺ , 7), 341 (92), 339 (100)

7-Bromo-1-(pyrrolidin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine (4):

A solution of compound 3 (2.2 g, 5.56 mmol) in MeOH (solv. The reaction was brought to room temperature, the methanol was evaporated and the solution was basified with 6N NaOH (pH~14). The product was extracted into _{CH 2 Cl 2 (3 × 50mL} ) and the combined organic layers were dried (Na ₂ SO ₄₎ and concentrated to give 4 (1.49g, 91%) of the crude product slurry. ¹ H NMR (DMSO- d ₆ ) δ 1.47-1.62 (m, 6H), 1.97-2.08 (m, 1H), 2.59-2.68 (m, 3H), 2.73-2.79 (m, 2H), 2.84-2.88 ( m, 2H), 3.08-3.09 (m, 1H), 3.78-3.87 (m, 1H), 6.85 (d, 1H, J = 8.4 Hz), 7.22 (dd, 1H, J = 2.4, 8.4 Hz), 7.26 (d, 1H, J = 2.4 Hz); ESI-MS (m/z, %): 297,295 (M ⁺ , 100)

7-Bromo-1-(1-methylpyrrolidin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine (5):

Compound 4 (0.79g, 2.68mmol) in anhydrous methanol (10mL) of solution, formaldehyde (37% in H ₂ O, 0.26g, 3.22mmol) processing, and then acetic acid (0.38mL, 6.707mmol) and NaCNBH ₃ (0.20 g, 3.22 mmol) was taken at room temperature. The reaction mixture was stirred at room temperature overnight (16 h). The reaction was extracted into _{CH 2 Cl 2 (2 × 25mL} ) in 2N NaOH (50mL) and basified and the product. The combined organic layers were washed with brine (25mL), dried (Na ₂ SO ₄₎ and concentrated. The crude product was purified by column chromatography to (CH ₂ Cl _2, then to 2N NH ₃ in _{MeOH: CH 2 Cl 2, 5} : 95) to give compound 5 (0.74g, 90%) as a brown solid. ¹ H NMR (DMSO- d ₆ ) δ 1.48-1.49 (m, 2H), 1.59-1.72 (m, 3H), 2.22 (s, 3H), 2.54-2.66 (m, 5H), 2.89-2.90 (m, 2H), 3.33 (brs, 2H), 3.90-3.94 (m, 1H), 6.78 (d, 1H, J = 8.5 Hz), 7.20 (dd, 1H, J = 2.5, 8.5 Hz), 7.26 (d, 1H) , J = 2.5 Hz); ESI-MS (m/z, %): 311 (MH ⁺ , 97), 309 (100)

1-(1-Methylpyrrolidin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-7-amine (6):

The _{Pd 2 (dba) 3 (105mg} , 0.11mmol) and PtBu ₃ (10% wt in hexanes, 1.40mL, 0.46mmol) in dry THF (5mL) suspension of, compound 5 (713mg, 2.30mmol) in This was treated with THF (10 mL) EtOAc (EtOAc)EtOAc. The resulting dark brown mixture was heated to 100 ° C in a sealed tube and stirred for 3 hours. The reaction mixture was cooled to rt EtOAc (EtOAc)EtOAc. The product was extracted into _{CH 2 Cl 2 (2 × 50mL} ), the combined organic portions were washed with brine (25mL), dried (MgSO _4), filtered and concentrated to give a dark brown residue. The crude product was purified by column chromatography (2N NH ₃ in _{MeOH: CH 2 Cl 2, 5} : 95) in order to obtain a compound 6 (531mg, 94%) pulp.

N-(1-(1-methylpyrrolidin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[b]hydroindol-7-yl)thiophene-2-carboxyindole Amine amide (46):

Compound 6 (494mg, 2.01mmol) in absolute ethanol (10 mL) of the solution, compound 7 (1.15g, 4.03mmol) processing, and stirred at room temperature overnight (16h). The reaction mixture was diluted with saturated NaHCO ₃ solution (100 mL) and in _{CH 2 Cl 2 (2 × 50mL} ) and extracted. The combined organic portions were washed with brine (25mL), dried (MgSO _4), filtered and concentrated. The crude product was purified by column chromatography to in _{(MeOH: CH 2 Cl 2,} 2: 98, then to 2N NH ₃ in _{MeOH: CH 2 Cl 2, 2.5} : 97.5, then 5:95) to give Compound 46 (559mg, 78%) solid. ¹ H NMR (DMSO- d ₆ ) δ 1.50-1.51 (m, 2H), 1.65-1.72 (m, 3H), 2.13-2.17 (m, 1H), 2.24 (s, 2H), 2.32 - 2.35 (m, 1H), 2.63-2.70 (m, 5H), 2.83-2.90 (m, 2H), 3.21 (s, 1H), 3.92-3.96 (m, 1H), 6.31 (brs, 2H), 6.60-6.68 (m, 2H), 6.78-6.92 (m, 1H), 7.06-7.11 (m, 1H), 7.56-7.60 (m, 1H), 7.69-7.72 (m, 1H); ESI-MS (m/z, %): 355 (MH ⁺ , 83), 272 (100), 178 (82); ESI-HRMS calc. for C ₂₀ H ₂₇ N ₄ S (MH ⁺ ), calc.: 355.1960; observed: 355.1950; HPLC purity: 92.12% area.

Example 47

4-(3,4-dihydroquinolin-1(2H)-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

1,2,3,4-tetrahydroquinoline (1.06 g, 7.51 mmol) and a third butyl 4-oxopyrrolidine-1-carboxylate (2.24 g, 11.26 mmol) in 20 mL 1,2 A solution of dichloroethane was treated with sodium triethoxysulfonate hydride (4.77 g, 22.53 mmol) and then acetic acid (1. The suspension was stirred at room temperature overnight. At this point, TLC analysis showed that 1,2,3,4-tetrahydroquinoline was present along with a more polar spot. To the reaction mixture was added 4-butyloxypiperidine-1-carboxylic acid tert-butyl ester (1.12 g, 5.63 mmol) and sodium triethoxysulfonylborohydride (2.39 g, 11.28 mmol). The suspension was stirred at room temperature for 4 days. The mixture was then cooled to 0 ° C, quenched with 20 mL 1 N NaOH and stirred for 20 min. The organic layer was separated and the aqueous layer was extracted with 50 mL CH ₂ Cl ₂ . The combined organic layers were dried with sodium sulfate, filtered and evaporated The residue was purified using a Biotage purification system using a 40M column. The title compound (0.89 g, 37.4%) was obtained using EtOAc EtOAc EtOAc EtOAc ¹ H-NMR (CDCl ₃ ) δ 7.09-7.03 (m, 1H), 6.97-6.94 (m, 1H), 6.65 (d, J = 8.4 Hz, 1H), 6.60-6.55 (m, 1H), 4.30- 4.19 (m, 2H), 3.80-3.70 (m, 1H), 3.17 (t, J = 5.7 Hz, 2H), 2.84 - 2.71 (m, 2H), 2.73 (t, J = 6.3 Hz, 2H), 1.93 -1.85 (m, 2H), 1.78.63 (m, 4H), 1.48 (s, 9H). MS (ESI): 317.2 (M+1).

4-(6-bromo-3,4-dihydroquinolin-1(2H)-yl)piperidine-1-carboxylic acid tert-butyl ester

4- (3,4-dihydro-quinoline -1 (2H) - yl) piperidine-1-carboxylic acid tert-butyl ester (0.85g, 2.69mmol) in 15mL DMF the solution was cooled to 0 ℃, then a solution of NBS (478 mg, 2.69 mmol) was added in 12 mL DMF. The reaction was stirred at 0 ° C for 1 hour and then treated with 100 mL of H ₂ O. The suspension was extracted with 2 x 75 mL ethyl acetate. The combined organic layers were washed with brine (2×50 mL) dried over sodium sulfate. The residue was subjected to silica gel chromatography using a Biotage purification system (25+M column, 0-20% ethyl acetate / hexane over 10 column volume) to obtain a viscous oil, which was solidified to give a white solid (852 mg). , 80.4%). ¹ H-NMR (CDCl ₃ ) δ 7.10 (dd, J = 2.4 Hz, 8.7 Hz, 1.H), 7.05-7.04 (m, 1H), 6.51 (d, J = 9.0 Hz, 1H), 4.33-4.19 (m, 2H), 3.71-3.64 (m, 1H), 3.14 (t, J = 6.0 Hz, 2H), 2.82-2.74 (m, 2H), 2.69 (t, J = 6.3 Hz, 2H), 1.91 1.77 (m, 2H), 1.61-1.57 (m, 4H), 1.47 (s, 9H). MS (ESI): 395.1 and 377.1 (M + 1).

4-(6-Amino-3,4-dihydroquinolin-1(2H)-yl)piperidine-1-carboxylic acid tert-butyl ester

The _{Pd 2 (dba) 3 (29mg} , 0.032mmol) in 2mL of anhydrous THF suspension to PtBu ₃ (400μL 10% wt solution in hexanes, 0.13 mmol) and stirred at room temperature for 5 minutes. To this mixture was added tert-butyl 4-(6-bromo-3,4-dihydroquinolin-1(2H)-yl)pyrrolidine-1-carboxylate (250 mg, 0.63 mmol), followed by lithium six Methyl diazane (1.3 mL of 1 M solution in THF, 1.3 mmol). The dark brown suspension obtained was heated at 95 ° C for 3 hours. The mixture was cooled to room temperature and treated with 5 mL of 1M tetrabutyl ammonium fluoride solution in THF and then stirred at room temperature for 30 min. This mixture in ethyl acetate (100 mL) between H ₂ O (20mL) and the layers separated. After extraction, the organic layer was separated, dried over sodium sulfate, filtered and concentrated to give a dark brown residue. The residue was subjected to flash chromatography on silica, using 2.5% 2M NH ₃ in methanol / CH ₂ Cl ₂ to give a viscous dark brown residue (160mg, 76.6%). ¹ H-NMR (CDCl ₃ ) δ 6.56 (d, J = 8.4 Hz, 1H), 6.48 (dd, J = 2.7, 8.7 Hz, 1H), 6.43-6.42 (m, 1H), 4.25-4.21 (m, 2H), 3.69-3.59 (m, 1H), 3.24 (br s, 2H), 3.07 (t, J = 5.4 Hz, 2H), 2.78-2.72 (m, 2H), 2.66 (t, J = 6.6 Hz, 2H), 1.93-1.83 (m, 2H), 1.76-1.55 (m, 4H), 1.47 (s, 9H). MS (ESI): 332.2 (M+1, 100%).

Example 48

3- (7-bromo-2,3,4,5-tetrahydro -1H- benzo [b] Boom nitrogen-l-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (1): See implementation Example 46 has complete experimental details and spectral data 3-(7-Amino-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (2):

A suspension of Pd ₂ (dba) ₃ (0.13 g, 0.145 mmol) and PtBu ₃ (1.76 mL, 0.581 mmol, 10% wt in hexane) in anhydrous THF (5 mL), Compound 1 (1.15 g, 2.908 mmol It was treated with THF (15 mL solution, and then treated with LiHMDS (5.81 mL, 5.816 mmol, 1 M solution in THF) at room temperature. The obtained dark brown mixture was heated to 100 ° C in a sealed tube and stirred for 3 hours. The reaction mixture was cooled. To room temperature, and treated with TBAF (5 mL, 1 M solution in THF) and stirred for 20 min. The reaction was diluted with water (25 mL) and the product was taken up in ether (3 x 50 mL) and the combined organics were dried (Na ₂ SO ₄ ) and concentrated to give a dark brown residue. The crude product was purified by chromatography on silica gel (2N NH ₃ in methanol: CH ₂ Cl ₂ , 2:98) to give compound 2 (0.96 g, quantitative ¹ H NMR (CDCl ₃ ) δ 6.77 (d, 1H, J = 8.1 Hz), 6.52-6.44 (m, 2H), 3.97-3.86 (m, 1H), 3.70-3.40 (m, 2H), 3.32-3.09(m,2H), 2.85-2.77(m,2H), 2.70-2.62(m,2H),2.14-2.04(m,1H),1.90-1.72(m,1H),1.68-1.50(m , 4H), 1.44 (s, 9H); ESI-MS (m/z, %): 332 (MH ⁺ , 49), 276 (100)

Tert-butyl 3-(7-(thiophene-2-carboxyindoleamine)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)pyrrolidine- 1-carboxylate (4):

Compound 2 (0.94g, 2.836mmol) in absolute ethanol solution (25mL), the compound 3 (1.61g, 5.672mmol) and stirred at room temperature overnight treatment (16h). The reaction mixture was diluted with saturated NaHCO ₃ solution (50mL), and extracted into _{CH 2 Cl 2 (2 × 50mL} ). The combined organic portions were washed with brine (20mL) and dried (Na ₂ SO _4). The solvent was evaporated, and the crude product was purified by column chromatography to (2N NH ₃ in _{MeOH: CH 2 Cl 2, 2.5} : 97.5) to give compound 4 (1.05g, 85%) foam. ¹ H NMR (CDCl ₃ ) δ 7.44-7.36 (m, 2H), 7.07 (dd, 1H, J = 3.6, 5.1 Hz), 6.93 (d, 1H, J = 8.1 Hz), 6.80-6.72 (m, 2H) ), 4.85 (brs, 2H), 4.03-3.97 (m, 1H), 3.75-3.48 (m, 2H), 3.31-3.18 (m, 2H), 2.90-2.84 (m, 2H), 2.76-2.72 (m , 2H), 2.21-2.11 (m, 1H), 1.98-1.87 (m, 1H), 1.70-1.52 (m, 4H), 1.46 (s, 9H); ESI-MS (m/z, %): 441 (MH ⁺ , 100).

N-(1-(pyrrolidin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-7-yl)thiophene-2-carboxyindoleimide 48):

A solution of compound 4 (0.8 g, 1. EtOAc) (EtOAc) (EtOAc) The reaction was brought to room temperature and the solvent was evaporated. The crude product was dissolved in water (10 mL) filtered and washed. Water was evaporated to give compound 48 (0.7 g, 93%). ¹ H NMR (DMSO- d ₆ ) δ 11.44 (s, 1H), 9.78-9.65 (m, 3H), 8.78 (s, 1H), 8.17-8.15 (m, 2H), 7.37 (t, 1H, J = 4.2 Hz), 7.20-7.08 (m, 3H), 3.50-3.40 (m, 1H), 3.38-3.26 (m, 1H), 3.17-2.90 (m, 4H), 2.76 (brt, 2H), 2.30-2.20 (m, 1H), 2.00-1.90 (m, 1H), 1.70-1.50 (m, 4H); ESI-MS (m/z, %): 341 (MH ⁺ , 38), 272 (100); HRMS calcd for _{C 19 H 25 N 4 S (} MH +, free base), calculated: 341.1794; observations: 341.1801; HPLC purity: 98.20% area.

Example 49

3-(porphyrin-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (2):

Compound 1 (1.88mL, 16.782mmol), N -Boc-3- pyrrolidone (3.73g, 20.139mmol) in anhydrous methanol (20mL) of solution, acetic acid (2.37mL, 41.956mmol) to then NaCNBH ₃ ( 1.26 g, 20.139 mmol) was treated at 0 °C. The reaction was brought to room temperature and stirred for 3 h. The reaction solution was extracted into 1N NaOH _{CH 2 Cl 2 (3 × 25mL} ) (100mL) and basified and the product. The combined CH ₂ Cl ₂ layer was dried (Na ₂ SO ₄₎ and the solvent evaporated to give the crude product. The crude product was purified by column chromatography (ethyl acetate: hexane, 1:9) to yield Compound 2 (4.2 g, 87%). ¹ H NMR (CDCl ₃ ) δ 7.08-7.02 (m, 2H), 6.66 (t, 1H, J = 7.5 Hz), 6.49 (d, 1H, J = 7.8 Hz), 4.17-4.05 (m, 1H), 3.70-3.51 (m, 2H), 3.47-3.37 (m, 4H), 2.95 (t, 2H, J = 8.4 Hz), 2.18-1.99 (m, 2H), 1.46 (s, 9H); ESI-MS ( m/z, %): 289 (MH ⁺ , 16), 233 (100).

3-(5-bromoporphyrin-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (3):

A solution of compound 2 (4.15 g, 14.390 mmol) eluted EtOAc. The reaction was diluted with water (150 mL) and EtOAc (EtOAc) The combined ethyl acetate layers with water (2 × 25mL), brine (25mL) and dried (Na ₂ SO _4). The solvent was evaporated and the crude product was purified by column chromatography (ethyl acetate: hexane, 1: 4) to give compound 3 (5.12g, 97%) pulp. ¹ H NMR (CDCl ₃ ) δ 7.18-7.07 (m, 2H), 6.33 (d, 1H, J = 8.7 Hz), 4.13-3.99 (m, 1H), 3.68-3.26 (m, 6H), 2.94 (t , 2H, J=8.1Hz), 2.17-1.99 (m, 2H), 1.46 (s, 9H); ESI-MS (m/z, %): 390 (MNa ⁺ , 6), 368 (MH ⁺ , 3 ), 313, 311 (100).

3-(5-Aminoporphyrin-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (4):

A suspension of Pd ₂ (dba) ₃ (0.124 g, 0.136 mmol) and PtBu ₃ (1.65 mL, 0.544 mmol, 10% wt in hexane) in anhydrous THF (5 mL), Compound 3 (1.0 g, 2.722 mmol) A solution of THF (15 mL) was taken up in EtOAc (EtOAc:EtOAc: The dark brown mixture obtained was heated to 100 ° C in a sealed tube and stirred for 3 hours. The reaction mixture was cooled to room temperature and treated with TBAF (5 mL, 1 M solution in THF) and stirred for 20 min. The reaction was diluted with water (25mL) and the product was extracted into ether (3 × 30mL) and the combined organic portion was dried (Na ₂ SO ₄₎ and concentrated to give a dark brown residue. The crude product was purified by column chromatography to (2N NH ₃ in _{methanol: CH 2 Cl 2, 3:} 97) to give compound 4 (0.68g, 82%) foam. ESI-MS (m/z, %): 304 (MH ⁺ , 16), 248 (100), 134 (25)

3-(5-(thiophene-2-carboxyindolinamine) porphyrin-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (6):

Compound 4 (0.65g, 2.142mmol) in absolute ethanol (15mL) of solution of compound 5 (1.22g, 4.284mmol) and stirred at room temperature overnight treatment (16h). The reaction mixture was diluted with saturated NaHCO ₃ solution (50mL), and extracted into _{CH 2 Cl 2 (2 × 50mL} ). The combined organic portions were washed with brine (20mL) and dried (Na ₂ SO _4). The solvent was evaporated, and the crude product was purified by column chromatography to (2N NH ₃ in _{methanol: CH 2 Cl 2, 5:} 95) to give compound 6 (0.68g, 77%) foam. ¹ H NMR (DMSO- d ₆ ) δ 7.42-7.36 (m, 2H), 7.06 (dd, 1H, J = 3.6, 4.9 Hz), 6.79 (brs, 1H), 6.71 (t, 1H, J = 5.1 Hz ), 6.48 (d, 1H, J = 8.1 Hz), 4.89 (brs, 2H), 4.12-4.02 (m, 1H), 3.68-3.35 (m, 6H), 2.93 (t, 2H, J = 8.1 Hz) , 2.14 - 2.04 (m, 2H), 1.46 (s, 9H); ESI-MS (m/z, %): 413 (MH ⁺ , 100)

N-(1-(pyrrolidin-3-yl)porphyrin-5-yl)thiophene-2-carboximine amide (49):

A solution of compound 6 (0.35 g, 0.848 mmol) elute The reaction was brought to room temperature and the solvent was evaporated. The crude product was dissolved in water (10 mL) filtered and washed. The water was evaporated to give compound 49 (0.3 g, 92%). ¹ H NMR (DMSO- d ₆ ) δ 11.25 (s, 1H), 9.82-9.60 (m, 3H), 8.63 (s, 1H), 8.15-8.13 (m, 2H), 7.36 (t, 1H, J) =4.5Hz), 7.12-7.06(m,2H), 6.68(d,1H,J=8.4Hz), 4.39-4.35(m,1H),3.56-3.06(m,6H),2.96(t,2H, J=8.1 Hz), 2.18-2.00 (m, 2H); ESI-MS (m/z, %): 313 (MH ⁺ , free base, 100), 244 (61); ESI-HRMS calculated for C _{17 H 21 N 4 S (MH} +, free base), calculated: 313.1481; observations: 313.1473; HPLC purity: 94.05% area.

Example 50

Third butyl 3-(5-bromopyridin-1-yl)pyrrolidine-1-carboxylate (1):

See 49 of Example complete experimental details and spectral data

5-bromo-1-(pyrrolidin-3-yl)porphyrin (2):

A solution of compound 1 (3.0 g, 8.. <RTI ID=0.0></RTI></RTI><RTIgt; The reaction was brought to room temperature and the solvent was evaporated. The crude product was basified with 1N NaOH solution (pH ~ 14) and the product was extracted into _{CH 2 Cl 2 (3 × 25mL} ). The combined CH ₂ Cl ₂ layers were dried (Na ₂ SO ₄ ) and solvent was evaporated to give compound 2 (1.75 g, 80%). ¹ H NMR (DMSO- d ₆ ) δ 7.12-7.06 (m, 2H), 6.45 (d, 1H, J = 8.1 Hz), 4.00 - 3.92 (m, 1H), 3.34 (t, 2H, J = 8.4 Hz ), 2.96-2.66 (m, 7H) , 1.92-1.80 (m, 1H), 1.69-1.60 (m, 1H); ESI-MS (m / z,%): 267,269 (MH +, 100)

5-bromo-1-(1-methylpyrrolidin-3-yl)porphyrin (3):

Compound 2 (1.0g, 3.743mmol) in anhydrous methanol (10 mL), the order HCHO (0.36g, 4.491mmol, 37% in water), and then acetic acid (0.53mL, 9.357mmol), and NaCNBH ₃ (0.28g , 4.491 mmol) was treated at room temperature and the mixture obtained was stirred overnight (14 h). The reaction was basified with 2N NaOH solution and extracted into _{CH 2 Cl 2 (2 × 25mL} ) (50mL) and the product. The combined organic layers were washed with brine (15mL) and dried (Na ₂ SO _4). The solvent was evaporated and the crude product was purified by column chromatography to (2M NH ₃ in _{methanol: CH 2 Cl 2, 5:} 95) to give compound 3 (0.7g, 66.6%) pulp. ¹ H NMR (CDCl ₃ ) δ 7.12-7.08 (m, 2H), 6.35 (d, 1H, J = 9.0 Hz), 4.19 - 4.10 (m, 1H), 3.45 - 3.39 (m, 2H), 2.91 (t , 2H, J=8.1Hz), 2.70-2.63 (m, 3H), 2.51-2.43 (m, 1H), 2.34 (s, 3H), 2.19-2.07 (m, 1H), 1.93-1.81 (m, 1H) ); ESI-MS (m/z, %): 281, 283 (MH ⁺ , 100)

1-(1-Methylpyrrolidin-3-yl)porphyrin-5-amine (4):

A suspension of Pd ₂ (dba) ₃ (0.1 g, 0.113 mmol) and PtBu ₃ (1.38 mL, 0.45 mmol, 10% wt in hexanes) in anhydrous THF (3 mL), Compound 3 (0.64 g, 2.276 mmol) A solution of THF (7 mL) was taken up in EtOAc (EtOAc:EtOAc: The dark brown mixture obtained was heated to 100 ° C in a sealed tube and stirred for 3 hours. The reaction mixture was cooled to room rt and was taken &lt The reaction was extracted into 2N NaOH solution (25mL) and basified and the product _{CH 2 Cl 2 (3 × 20mL} ) and the combined organic portion washed with brine (20mL) and dried (Na ₂ SO _4). The solvent was evaporated and the crude product was purified by column chromatography on silica (2N NH ₃ in _{MeOH: CH 2 Cl 2, 5} : 95) to give compound 4 (0.44g, 89%) pulp. ¹ H NMR (DMSO- d ₆ ) δ 6.38 (s, 1H), 6.30-6.23 (m, 2H), 4.31 (brs, 2H), 4.01-3.92 (m, 1H), 3.14 (t, 2H, J = 8.1 Hz), 2.68 (t, 2H, J = 8.1 Hz), 2.56-2.50 (m, 3H), 2.37-2.29 (m, 1H), 2.21 (s, 3H), 2.02-1.90 (m, 1H), 1.76-1.66 (m, 1H); ESI-MS (m/z, %): 218 (MH ⁺ , 100)

N-(1-(1-methylpyrrolidin-3-yl)porphyrin-5-yl)thiophene-2-carboxyindoleimine amide (50):

Compound 4 (0.4g, 1.840mmol) in absolute ethanol (10 mL) of the solution, compound 5 (1.04g, 3.681mmol) and stirred at room temperature overnight treatment (16h). The reaction mixture was diluted with saturated NaHCO ₃ solution (25mL), and extracted into _{CH 2 Cl 2 (2 × 25mL} ). The combined organic portions were washed with brine (20mL) and dried (Na ₂ SO _4). The solvent was evaporated, and the crude product was purified by column chromatography to (2N NH ₃ in _{MeOH: CH 2 Cl 2, 5} : 95) to give compound 50 (0.43g, 72%) solid. ¹ H NMR (DMSO- d ₆ ) δ 7.68 (d, 1H, J = 3.0 Hz), 7.58 (dd, 1H, J = 1.2, 5.1 Hz), 7.07 (dd, 1H, J = 3.6, 4.9 Hz), 6.62(s,1H),6.52-6.48(m,2H),6.32(brs,2H),4.16-4.08(m,1H), 3.32-3.24(m,2H),2.81(t,2H,J=8.1 Hz), 2.63-2.55 (m, 3H), 2.38-2.31 (m, 1H), 2.24 (s, 3H), 2.09-1.97 (m, 1H), 1.82-1.71 (m, 1H); ESI-MS ( m / z,%): 327 (MH +, 100), 244 (83); ESI-HRMS calcd for _{C 18 H 23 N 4 S (} MH +), calcd: 327.1637; observations: 327.1650; HPLC Purity: 95.54% area.

Example 51

1-(6-bromo-3,4-dihydroquinolin-1(2H)-yl)-2-chloroethanone

A solution of 6-bromo-1,2,3,4-tetrahydroquinoline (2.09 g, 9.85 mmol) in 55 mL of toluene was added dropwise with 2-chloroethylhydrazine chloride (0.863 mL, 10.84 mmol) for 10 min. . The resulting suspension was stirred at room temperature for 1.5 hours and then heated at 95 ° C for 30 minutes. After cooling to room temperature, the yellow solution was diluted with 20 mL of ethyl acetate and was then taken to 25 <RTIgt; This mixture was poured into a separatory funnel. The organic layer was separated, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel using 30% ethyl acetate: 70% hexane as eluent. After drying under reduced pressure, a white solid was obtained (yield: 2.4 g, 84%). ¹ H-NMR (CDCl ₃ ) δ 7.35-7.33 (m, 3H), 4.19 (s, 2H), 3.80 (t, J = 6.3 Hz, 2H), 2.74 (t, J = 6.6 Hz, 2H), 2.041 .98 (m, 2H).

1-(6-bromo-3,4-dihydroquinolin-1(2H)-yl)-2-(ethyl(methyl)amino)ethanone

A suspension of 1-(6-bromo-3,4-dihydroquinolin-1(2H)-yl)-2-chloroethanone (1 g, 3.47 mmol) and potassium iodide (0.115 g, 0.693 mmol) in 10 mL THF Treated with N -methylethylamine (1.786 mL, 20.79 mmol). The mixture was stirred at room temperature for 2 hours and then heated at 65 ° C for 1 hour. The mixture was concentrated, and then partitioned between CH ₂ Cl ₂ (100 mL) and saturated sodium bicarbonate (25mL). After extraction, the organic layer was separated, dried over sodium sulfate, filtered and concentrated to give a pale brown residue. The residue was subjected to flash chromatography on silica, using 5% 2M NH ₃ in methanol / 95% CH ₂ Cl ₂ to give a light brown residue (1.06g, 98%). ¹ H-NMR (CDCl ₃ ) δ 7.52-7.40 (br s, 1H), 7.30-7.27 (m, 2H), 3.80 (t, J = 6.0 Hz, 2H), 3.28 (s, 2H), 2.72 (t) , J=6.9Hz, 2H), 2.50 (quart, J=7.2Hz, 2H), 2.30(s, 3H), 1.96 (quint, J=6.6Hz, 2H), 1.03(t, J=7.2Hz, 3H ). MS (ESI): 311.1 and 313.1 (M+1, 100%).

2-(6-Bromo-3,4-dihydroquinolin-1(2H)-yl)-N-ethyl-N-methylethylamine

1-(6-Bromo-3,4-dihydroquinolin-1(2H)-yl)-2-(ethyl(methyl)amino)ethanone (1.05 g, 3.37 mmol) in THF (10 mL ) the solution was cooled to 0 ℃, then BH ₃ in THF (1M) (33.7mL, 33.7mmol ) process. The clear solution was allowed to warm to room temperature and stirred at this temperature for 3 days. The mixture was cooled to 0.degree. C. and treated with EtOAc (5 mL). After stirring for 15 minutes, the mixture was concentrated to dryness then EtOAc m. The residue was dissolved in 25 mL of methanol and heated to reflux for 5 hr then stirred overnight at room temperature. The reaction was concentrated to dryness to give a pale yellow residue. The residue was subjected to flash chromatography on silica, using 5% 2M NH ₃ CH in MeOH / 95% ₂ Cl ₂ to give a colorless residue (0.89g, 89%). ¹ H-NMR (CDCl ₃ ) δ 7.09 (dd, J = 1.8, 6.6 Hz, 1H), 7.02-7.01 (m, 1H), 6.44 (d, J = 6.6 Hz, 1H), 3.36 (t, J = 5.7 Hz, 2H), 3.29 (t, J = 4.2 Hz, 2H), 2.70 (t, J = 4.8 Hz, 2H), 2.53-2.43 (m, 4H), 2.28 (s, 3H), 1.94-1.88 ( m, 2H), 1.06 (t, J = 5.4 Hz, 3H). MS (ESI): 397.1 and 399.1 (M+1, 100%).

1-(2-(ethyl(methyl)amino)ethyl)-1,2,3,4-tetrahydroquinolin-6-amine

a solution of 2-(6-bromo-3,4-dihydroquinolin-1(2H)-yl)-N-ethyl-N-methylethylamine (500 mg, 1.682 mmol) in THF (15 mL) This was treated with bis(dibenzylideneacetone)dipalladium(0) (77 mg, 0.084 mmol) eluting with tri-tert-butylphosphane as hexane (10% wt) (0.612 mL, 0.202 mmol). The resulting purple mixture was treated with LiHMDS (hexamethyldiaminolamidolithium), 1M in THF (5.05 mL, 5.05 mmol). The reaction vial was sealed and the dark mixture was heated at 90 °C for 2 hours. The mixture was transferred to a 125 mL flask, cooled to 0 ° C and treated with 10 mL of 2N HCl solution. After stirring for 10 minutes, the mixture was basified with 1N NaOH and extracted with 2×75 mL CH ₂ Cl ₂ . After extraction, the combined organic layers were dried with sodium sulfate, filtered and concentrated to give a dark residue. The residue was subjected to flash chromatography on silica using 2.5% methanol /97.5% CH ₂ Cl _2, followed by 5% 2M NH ₃ in methanol / 95% CH ₂ Cl ₂ to give a dark brown residue (351mg, 89%) . ¹ H-NMR (CDCl ₃ ) δ 6.49-6.48 (2H), 6.41 (br s, 1H), 3.36-3.31 (m, 2H), 3.21 (t, J = 5.7 Hz, 2H), 3.20 (br s, 2H), 2.68 (t, J = 6.3 Hz, 2H), 2.56-2.43 (m, 4H), 2.28 (s, 3H), 1.95-1.87 (m, 2H), 1.07 (t, J = 7.2 Hz, 3H) ). MS (ESI): 234.2 (M+1).

N-(1-(2-(ethyl(methyl)amino)ethyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboximine amide ( 51)

a solution of 1-(2-(ethyl(methyl)amino)ethyl)-1,2,3,4-tetrahydroquinolin-6-amine (335 mg, 1.436 mmol) in ethanol (15 mL) Part of the treatment with methylthiophene-2-carboquinone thiocarboxylate hydrogen iodide (819 mg, 2.87 mmol). The mixture was stirred at room temperature overnight. The mixture was partitioned between 100mL CH ₂ Cl ₂ CO ₃ solution and 20mL ₂ saturated Na. After extraction, the organic layer was separated, dried over sodium sulfate, filtered and concentrated to give a yellow brown residue. The residue was subjected to flash chromatography on silica using 2.5% methanol /97.5% CH ₂ Cl ₂ then 5% 2M NH ₃ in methanol / 95% CH ₂ Cl ₂ to give a dark yellow residue (360mg, 73.2%). ¹ H-NMR (DMSO-d ₆ ) δ 7.67 (d, J = 3.6 Hz, 1H), 7.55 (dd, J = 0.9, 5.1 Hz, 1H), 7.07 (dd, J = 3.6, 4.8 Hz, 1H) , 6.58-6.48 (3H), 6.30 (br s, 2H), 3.30-3.22 (m, 4H), 2.65 (t, J = 6.0 Hz, 2H), 2.46-2.36 (m, 4H), 2.20 (s, 3H), 1.87-1.80 (m, 2H), 0.97 (t, J = 7.2 Hz, 3H). MS (ESI): 343.2 (M+1). ESI-HRMS calculated for C ₁₉ H ₂₇ N ₄ S (MH ⁺ ): 343.1950, observed: 343.1946.

Example 52

8-fluoro-6-nitro-3,4-dihydroquinolin-2(1H)-one

To a stirred solution of 8-fluoro-3,4-dihydro-quinolin -2 (1H) - one solution (see Examples 41 details application) (2g, 12.11mmol) in sulfuric acid (12ml), the cooled to -5 At ° C, nitric acid was added as a 1:1 solution of 90% (0.565 ml, 12.11 mmol) in water. The reaction mixture was stirred at -5 °C for 20 minutes, then quenched with ice and then the product was collected by filtration. The gray solid was dissolved in dichloromethane, dried, filtered and concentrated, and chromatographed on silica gel, using 0-10% ethyl acetate in dichloromethane as eluent to give the desired 8-fluoro-6-nitro group. -3,4-Dihydroquinolin-2(1H)-one (2.33 g, 11.09 mmol, 92% yield). ¹ H NMR (DMSO- d ₆ ) δ 10.73 (brs, 1H), 8.03 (m, 1H), 8.02 (m, 1H), 3.08 (t, J = 7.5 Hz, 2H), 2.57 (t, J = 7.5) Hz, 1H)

8-fluoro-6-nitro-1,2,3,4-tetrahydroquinoline

Add a solution of borane-tetrahydrofuran in a stirred solution of 8-fluoro-6-nitro-3,4-dihydroquinolin-2(1H)-one (950 mg, 4.52 mmol) in tetrahydrofuran (5 ml) (45.2 ml, 45.2 mmol) in THF. The reaction mixture was allowed to warm to reflux temperature overnight. The reaction mixture was then cooled to 0 ° C and quenched with methanol. The quenched mixture was concentrated in vacuo, red-br. This mixture was concentrated on silica gel and chromatographed using 0-20% ethyl acetate in hexane. ¹ H NMR (DMSO- d ₆ ) δ 7.77-7.71 (m, 1H), 7.73 (m, 1H), 7.31 (brs, 1H), 3.35-3.28 (m, 2H), 2.77 (t, J = 6.2 Hz) , 2H), 1.85-1.77 (m, 2H)

2-(8-Fluoro-6-nitro-3,4-dihydroquinolin-1(2H)-yl)-N,N-dimethylethylamine

A solution of 8-fluoro-6-nitro-1,2,3,4-tetrahydroquinoline (670 mg, 3.42 mmol) in N,N -dimethylformamide (15 ml) was stirred. To 0 ° C, sodium hydride, 60% (437 mg, 10.93 mmol) was added while stirring vigorously. When the foaming subsided, 2-chloro- N,N -dimethylethylamine hydrogen chloride (984 mg, 6.83 mmol) was added, and the reaction mixture (dark red) was stirred at room temperature. After 2 hours, no product was observed, so the reaction was heated to 90 ° C and stirred. After 1 h, TLC showed the reaction was completed. The mixture was then cooled to room temperature, diluted with water and extracted with ethyl acetate (3x). The combined organic phases were washed with 1:1 water: brine (2x) then brine (1x). The organic phase was dried, filtered and concentrated, then chromatographed in 0-10% (2M NH ₃ in methanol) in 1: 1 ethyl acetate: dichloromethane, to give the look of 2- (8-fluoro-6-nitro - 3,4-Dihydroquinolin-1(2H)-yl)-N,N-dimethylethylamine (514 mg, 1.923 mmol, 56.3% yield). NMR (DMSO- d ₆ ) δ 7.77 (dd, J = 15 Hz, 2.7 Hz, 1H); 7.72 (m, 1H); 3.55-3.48 (m, 2H); 3.43-3.39 (m, 2H); 2.78-2.74 (m, 2H), 2.49-2.44 (m, 2H); 2.16 (s, 6H); 1.88-1.79 (m, 2H). ESI-MS (m/z, %): 268 (MH+, 100); 223 (5)

Phenyl 2-(8-fluoro-6-nitro-3,4-dihydroquinolin-1(2H)-yl)ethyl(methyl)aminecarboxylate

2-(8-Fluoro-6-nitro-3,4-dihydroquinolin-1(2H)-yl)-N,N-dimethylethylamine (500 mg, 1.871 mmol) A solution of dichloromethane (8 ml) was slowly added dropwise phenyl chloroformate (0.352 ml, 2.81 mmol) via a syringe at room temperature. The resulting solution was stirred at room temperature overnight. The reaction mixture was then diluted with water and brine (3×). The combined organics were dried, filtered and concentrated then purified eluting elut elut -1(2H)-yl)ethyl(methyl)carbamate (576 mg, 1.543 mmol, 82% yield). ¹ H NMR (DMSO- d ₆ ) δ 7.85-7.76 (m, 1H); 7.75-7.70 (m, 1H); 7.34 (t, J = 7 Hz, 1H); 7.22 - 7.16 (m, 1H); 6.95 (m, 2H); 3.77-3.65 (m, 3H); 3.60-3.54 (m, 1H); 3.43 (t, J = 5.5 Hz, 2H); 3.02, 2.93 (2s, 3H); 2.75 (t, J = 5.8, 2H); 1.90 - 1.81 (m, 2H). ESI-MS (m/z, %): 374 (MH+, 100)

Phenyl 2-(6-amino-8-fluoro-3,4-dihydroquinolin-1(2H)-yl)ethyl(methyl)aminecarboxylate

Phenyl 2-(8-fluoro-6-nitro-3,4-dihydroquinolin-1(2H)-yl)ethyl(methyl)aminecarboxylate (560 mg, 1.500 mmol) Solution, palladium on activated carbon, 10 wt% (160 mg, 0.150 mmol). The resulting suspension was stirred at room temperature under a hydrogen balloon pressure atmosphere. After 3 h, most of the starting material was consumed and the reaction stopped due to the presence of small amounts of impurities. The reaction mixture was filtered through a pad of celite and concentrated to give a brown oil. The residue is dried and used directly in the subsequent reaction. The crude product phenyl 2-(6-amino-8-fluoro-3,4-dihydroquinolin-1(2H)-yl)ethyl(methyl)amine formate (449 mg, 1.308 mmol, 87) was obtained. %Yield). ¹ H NMR (DMSO- d ₆ ) δ 7.40-7.35 (m, 2H); 7.23-7.17 (m, 1H); 7.10-7.05 (m, 2H); 6.19 (d, J = 14 Hz, 1H); s, 1H); 4.85-4.72 (m, 2H); 3.57-3.53 (m, 1H); 3.46-3.42 (m, 1H); 3.13-2.93 (m, 4H); 3.07, 2.95 (2s, 3H); 2.57 (t, J = 6.3 Hz, 1H); 1.74-1.65 (m, 2H). ESI-MS (m/z, %): 344 (MH+)

2-(8-Fluoro-6-(thiophene-2-carboxyindoleamine)-3,4-dihydroquinolin-1(2H)-yl)ethyl(methyl)aminecarboxylate (52 )

Benzyl 2-(6-amino-8-fluoro-3,4-dihydroquinolin-1(2H)-yl)ethyl(methyl)aminecarboxylate (426 mg, 1.241 mmol) A solution of ethanol (12 ml) was added with methylthiophene-2-carboquinone thiocarboxylate hydrogen iodide (708 mg, 2.481 mmol). The reaction mixture was stirred at room temperature under hydrogen overnight. The reaction mixture was then diluted with water and sodium carbonate then extracted with dichloromethane (3x). The combined organics were dried, filtered and concentrated then purified eluting elut elut Benzyl 3,4-dihydroquinolin-1(2H)-yl)ethyl(methyl)aminecarboxylate 52 (422 mg, 0.933 mmol, 75% yield). ¹ H NMR (DMSO- d ₆ ) δ 7.74-7.71 (m, 1H); 7.59-7.57 (m, 1H); 7.41-7.36 (m, 2H); 7.23-7.18 (m, 1H); 7.14-7.07 ( m, 3H); 6.50-6.42 (m, 3H); 6.37 (s, 1H); 3.62 (t, J = 6 Hz, 1H); 3.51 (t, J = 6 Hz, 1H); 3.30 (t, J = 6 Hz) , 1H); 3.23 (t, J = 6 Hz, 1H); 3.15-3.09 (m, 2H); 3.09, 2.97 (2s, 3H); 2.69 (t, J = 6 Hz, 2H); 1.83-1.75 (m, 2H). EI-MS (m/z, %): 452 (M+, 8); 288 (60); 179 (100)

N-(8-fluoro-1-(2-(methylamino)ethyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboxyindoleimine

2-(8-Fluoro-6-(thiophene-2-carboxyindoleamine)-3,4-dihydroquinolin-1(2H)-yl)ethyl(methyl)amine A solution of phenyl formate (400 mg, 0.884 mmol) in EtOAc (EtOAc) (EtOAc) The resulting mixture was stirred at reflux and monitored by TLC. After 3 h, the reaction mixture showed some product formed, as well as some starting material. Due to the formation of some by-products, the reaction was quenched, diluted with water and extracted with dichloromethane (3×). The combined organic phase was dried, filtered and concentrated, then chromatographed in 0-10% (2M NH ₃ in MeOH) in dichloromethane to give the look N- (8- fluoro-l- (2- (dimethylamino Ethyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboxyindoleimine amide (67 mg, 0.202 mmol, 22.80% yield). ¹ H NMR (DMSO- d ₆ ) δ 7.71 (d, J = 3, 1H); 7.58 (d, J = 5 Hz, 1H); 7.07 (dd, J = 5 Hz, 3 Hz, 1H); 6.48-6.43 (m) , 2H); 6.41 (brd, J = 15 Hz, 1H); 6.34 (s, 1H); 3.09 (m, 4H); 2.73 - 2.64 (m, 4H); 2.31 (s, 3H); 1.77-1.72 (m , 2H). EI-MS (m/z, %): 332 (M+, 9), 288 (100)

N-(8-fluoro-1-(2-(methylamino)ethyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboxyindoleimine amide Hydrogen chloride

N-(8-fluoro-1-(2-(methylamino)ethyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboxyindole in a stirred state A solution of the iminoamine (57 mg, 0.171 mmol) in MeOH (3 mL). The resulting solution was concentrated to give N-(8-fluoro-1-(2-(methylamino)ethyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2. - Carboxylimine indoleamine dihydrogen chloride (69 mg, 0.170 mmol, 99% yield). ¹ H NMR (DMSO- d ₆ ) δ 9.79 (s, 1H); 9.13 (brs, 2H); 8.84 (s, 1H); 8.16 (d, J = 4.8 Hz); 7.37 (t, J = 4.3 Hz, 1H); 7.14 (d, J = 14 Hz, 1H); 6.94 (s, 1H); 3.47-3.40 (m, 2H); 3.24 - 3.18 (m, 2H); 3.18-3.10 (m, 2H); 2.76 ( t, J = 6 Hz, 2H); 2.58 (t, J = 5.1 Hz, 3H); 1.85-1.78 (m, 2H). EI-MS (m/z, %): 332 (M+, 9); 288 (100). HRMS calculated for C17H21FN4S (M ⁺ ), calc.: 332.1477, observed: 332.1471. HPLC purity: 95%.

Example 53

1-(2-(Diethylamino)ethyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one

6-Nitro-3,4-dihydroquinolin-2(1H)-one ¹ (2 g, 10.41 mmol), 2-(diethylamino)ethyl chlorohydrochloride (2.69 g, 15.61 mmol), A suspension of potassium carbonate (6.47 g, 46.8 mmol) in DMF (25 mL) The mixture was diluted with water (50 mL) then extracted ethyl acetate (2×75 mL). The combined organic layers were washed with brine (2×20 mL) dried over sodium sulfate. The residue was subjected to flash chromatography on silica, using 2.5% 2M NH ₃ CH in methanol / 95% ₂ Cl ₂ and dried under reduced pressure to give a yellow solid (2.35g, 78%). ¹ H-NMR (CDCl ₃ ) δ 8.15 (dd, J = 2.7, 9.0 Hz, 1H), 8.06-8.05 (m, 1H), 7.30-7.25 (m, 1H), 4.09 (t, J = 6.9 Hz, 2H), 3.00 (t, J = 6.9 Hz, 2H), 2.73-2.60 (m, 8H), 1.03 (t, J = 7.2 Hz, 6H)

1. Devita et al, WO03/045313

N,N -diethyl-2-(6-nitro-3,4-dihydroquinolin-1(2H)-yl)ethylamine

1- (2- (diethylamino) ethyl) -6-nitro-3,4-dihydro-quinolin -2 (1H) - one (1g, 3.43mmol) and 1M BH ₃ in THF ( A solution of 17.16 ml, 17.16 mmol) was stirred at room temperature overnight. After that, the reaction was cooled to 0 ° C then treated with EtOAc (25 mL). The mixture was stirred at 0 ° C for 10 minutes and then concentrated with a vortex evaporator to give a yellow solid. This compound was dissolved in 40 mL of methanol and heated to reflux for 3 hr. After cooling, the solvent was evaporated, and the resulting yellow-brown residue was applied to flash chromatography on silica, using 5% 2M NH ₃ in methanol / 95% CH ₂ Cl ₂ to give a light yellow residue (0.87g, 91% ). ¹ H-NMR (CDCl ₃ ) δ 7.96 (dd, J = 2.7, 9.0 Hz, 1H), 7.85-7.84 (m, 1H), 6.51 (d, J = 9.0 Hz, 1H), 3.47 (t, J = 5.4 Hz, 4H), 2.74 (t, J = 6.3 Hz, 2H), 2.68-2.59 (m, 6H), 1.99-1.91 (m, 2H), 1.05 (t, J = 6.9 Hz, 6H). MS (ESI): 278.2 (M+1)

1-(2-(diethylamino)ethyl)-1,2,3,4-tetrahydroquinolin-6-amine

N,N -Diethyl-2-(6-nitro-3,4-dihydroquinolin-1(2H)-yl)ethylamine (0.85 g, 3.06 mmol) and palladium-carbon, 10% wt A suspension of (0.163 g, 0.153 mmol) in EtOAc (30 mL). This mixture was filtered through a pad of celite. The diatomaceous earth pad was rinsed with 20 mL of methanol. The filtrate was concentrated, and the residue was subjected to flash chromatography on silica gel using 5% 2M NH ₃ CH in methanol / 95% ₂ Cl ₂ to give a dark brown residue (685mg, 90%). ¹ H-NMR (CDCl ₃ ) δ 6.63-6.32 (m, 3H), 3.37-3.23 (m, 4H), 2.74 - 2.56 (m, 8H), 1.93 (t, J = 5.7 Hz, 2H), 1.08 ( t, J = 7.2 Hz, 6H). MS (ESI): 248.2 (M+1)

N-(1-(2-(Diethylamino)ethyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboxyindoleimide (53)

A solution of 1-(2-(diethylamino)ethyl)-1,2,3,4-tetrahydroquinolin-6-amine (670 mg, 2.71 mmol) in ethanol (25 mL) The thiophene-2-carboquinone thiocarboxylate hydrogen iodide (1545 mg, 5.42 mmol) was partially treated. The resulting suspension was stirred at room temperature overnight. The mixture was concentrated, then partitioned between in 150mL CH ₂ Cl ₂ CO ₃ solution and 40mL ₂ saturated Na. After extraction, the organic layer was separated, dried over sodium sulfate, filtered and concentrated to give a yellow brown residue. The residue was subjected to flash chromatography on silica gel, using 2.5-5% methanol/97.5-95% CH ₂ Cl ₂ followed by 5% 2M NH ₃ in methanol/95% CH ₂ Cl ₂ to give a dark yellow residue. It was solidified after pressure drying (670 mg of 53 , 69.4%). ¹ H-NMR (DMSO-d ₆ ) δ 7.67 (d, J = 3.0 Hz, 1H), 7.54 (d, J- 4.8 Hz, 1H), 7.07 (dd, J = 3.6, 4.5 Hz, 1H), 6.57 -6.48(m,3H), 5.76(br s,2H),3.32-3.25(m,4H),2.67-2.63(m,2H),2.52-2.48(m, 6H),1.86-1.82(m,2H) ), 0.97 (t, J = 6.9 Hz, 6H). MS (ESI): 357.2 (M+1). ESI-HRMS calculated for C ₂₀ H ₂₉ N ₄ S (MH ⁺ ): 357.2107, observed: 357.2110.

Example 54

Third butyl 4-(porphyrin-1-yl)piperidine-1-carboxylate (2):

Porphyrin 1 (2.0 g, 16.78 mmol), 4-butyloxypiperidine-1-carboxylic acid tert-butyl ester (3.68 g, 18.46 mmol) in anhydrous 1,2-dichloroethane (30 mL) was treated with acetic acid (2.4mL, 42.00mmol) process, then _{NaBH (OAc) 3 (5.34g,} 25.2mmol) treated at 0 ℃. The resulting mixture was brought to room temperature and stirred for 3 h. The reaction was basified in 1N NaOH solution (50 mL) and the product was taken to ethyl acetate (2×50mL). The combined ethyl acetate layer was washed with brine (25mL) and dried (Na ₂ SO _4). The solvent was evaporated and the crude product was purified by column chromatography (ethyl acetate: hexane, 1: 4) to give compound 2 (5.0g, 99%) pulp. ¹ H NMR (CDCl ₃ ) δ 7.05 (t, 2H, J = 7.8 Hz), 6.62 (t, 1H, J = 7.2 Hz), 6.43 (d, 1H, J = 7.5 Hz), 4.25 - 4.20 (m, 2H), 3.55-3.46 (m, 2H), 3.35 (t, 2H, J = 8.4 Hz), 2.95 (t, 2H, J = 8.4 Hz), 2.77 (t, 2H, J = 12.3 Hz), 1.81 1.77 (m, 2H), 1.63-1.51 (m, 2H), 1.47 (s, 9H); ESI-MS (m/z, %) 303 (MH ⁺ , 5), 247 (100).

4-(5-bromoporphyrin-1-yl)piperidine-1-carboxylic acid tert-butyl ester (3):

Compound 2 (2.0g, 6.61mmol) in dry DMF (10mL) of solution, to N - bromo-succinimide (PEI) (1.17g, 6.61mmol) in DMF (10mL) takes 30 minutes for treatment at 0 ℃. The reaction was stirred at the same temperature for 3.5 h. The reaction was diluted with water (200 mL) and EtOAc (EtOAc) The combined ethyl acetate layers with water (2 × 50mL), brine (25mL) and dried (Na ₂ SO _4). The solvent was evaporated and the crude product was purified by column chromatography (ethyl acetate: hexane, 1: 4) to give compound 3 (2.5g, 99%) pulp. ¹ H NMR (CDCl ₃ ) δ 7.13-7.10 (m, 2H), 6.27 (d, 1H, J = 9.0 Hz), 4.28 - 4.20 (m, 2H), 3.50 - 3.40 (m, 1H), 3.35 (t) , 2H, J=8.4Hz), 2.93(t, 2H, J=8.4Hz), 2.75(t, 2H, J=12.9Hz), 1.78-1.72(m, 2H), 1.60-1.49(m, 2H) , 1.46 (s, 9H); ESI-MS (m/z, %) 381, 383 (MH ⁺ , 3), 325, 327 (100).

4-(5-(thiophene-2-carboxyindolinamine) porphyrin-1-yl)piperidine-1-carboxylic acid tert-butyl ester (6):

The _{Pd 2 (dba) 3 (0.08g} , 0.087mmol) in dry THF (5mL) of the solution to _{PtBu 3 (1.06mL, 0.351mmol, 10} % in hexanes), and then to compound 3 (0.67g, 1.757mmol It was treated with anhydrous THF (5 mL) and LiHMDS (3.51 mL, 3.514 mmol) at room temperature. The resulting mixture was stirred at 100 ° C for 3 h in a sealed tube. The reaction was taken to room temperature and quenched with TBAF (5 mL, 1 M solution in THF). After stirring for 15 minutes, the solution was 1N NaOH solution (50mL) and basified and the product was extracted into _{CH 2 Cl 2 (3 × 20mL} ). The combined CH ₂ Cl ₂ layers were dried (Na ₂ SO ₄ ) and evaporated to give crude material. The crude product was purified by column chromatography to (2M NH ₃ in _{MeOH: CH 2 Cl 2, 2.5} : 97.5) to give compound 4 (0.4g, 72%) foam.

Compound 4 (0.38g, 0.683mmol) in absolute ethanol (10 mL) of the solution, compound 5 (0.68g, 2.394mmol) at room temperature, and the mixture thus obtained and it was stirred overnight. The reaction with saturated NaHCO ₃ solution (50mL) and basified and the product was extracted into _{CH 2 Cl 2 (2 × 25mL} ) and dried (Na ₂ SO _4). The solvent was evaporated and the crude product was purified by column chromatography to (2M NH ₃ in _{MeOH: CH 2 Cl 2, 5} : 95) to give compound 6 (0.43g, 85%) solid. ¹ H NMR (DMSO- d ₆ ) δ 7.72 (d, 1H, J = 3.0 Hz), 7.62 (d, 1H, J = 4.8 Hz), 7.10 (dd, 1H, J = 3.6, 4.9 Hz), 6.68 ( s, 1H), 6.59 (d, 1H, J = 8.1 Hz), 6.47 (d, 1H, J = 8.4 Hz), 4.05 (d, 2H, J = 12.3 Hz), 3.58-3.50 (m, 1H), 3.28-3.24 (m, 2H), 2.90-2.78 (m, 4H), 1.68 (d, 2H, J = 11.1 Hz), 1.50-1.36 (m, 11H); ESI-MS (m/z, %) 427 (MH ⁺ , 100)

N-(1-(piperidin-4-yl)porphyrin-5-yl)thiophene-2-carboxyindoleimine decylamine dihydrogen chloride (54):

A solution of compound 6 (0.23 g, 0.539 mmol) elute The reaction was brought to room temperature and the solvent was evaporated. The crude material was dissolved in water (10 mL) filtered and washed with water The combined water layer was evaporated to obtain ¹ H NMR compound 54 (0.18g, 84%) dihydrochloride _{salt. (DMSO- d 6) δ 11.21} (s, 1H), 9.64 (s, 1H), 9.20-9.04 (m , 2H), 8.60 (s, 1H), 8.15-8.12 (m, 2H), 7.36 (t, 1H, J = 4.5 Hz), 7.11 - 7.03 (m, 2H), 6.66 (d, 1H, J = 8.4 Hz), 3.86-3.74 (m, 1H), 3.44-3.32 (m, 4H), 3.06-2.92 (m, 4H), 1.98-1.78 (m, 4H); ESI-MS (m/z, %) 327 ^{(MH +, 100), 244} (81); ESI-HRMS calcd for _{C 18 H 23 N 4 S (} MH +), calcd: 327.1637; observations: 327.1636; HPLC purity: 98.86% area.

Example 55

8-fluoro-6-nitro-3,4-dihydroquinolin-2(1H)-one

The stirring of a 8-fluoro-3,4-dihydro-quinolin -2 (1H) - one (see details of Example 41), (5g, 30.3mmol) in sulfuric solution, cooled to -5 deg.] C, A mixture of fuming nitric acid (1.413 ml, 30.3 mmol) in water was added. The resulting mixture was stirred at -5 ° C for 20 minutes. After 20 minutes, the reaction was quenched with ice and the product collected by filtration was precipitated. The filter cake was dissolved in dichloromethane and a small amount of methanol, dried, filtered and concentrated on silica gel and then chromatographed, using 0-10% ethyl acetate in dichloromethane to give the desired 8-fluoro-6-nitro-3, 4-Dihydroquinolin-2(1H)-one (5.9 g, 28.1 mmol, 93% yield). ¹ H NMR (DMSO- d ₆ ) δ 10.73 (brs, 1H), 8.03 (m, 1H), 8.02 (m, 1H), 3.08 (t, J = 7.5 Hz, 2H), 2.57 (t, J = 7.5) Hz, 1H)

8-fluoro-6-nitro-1,2,3,4-tetrahydroquinoline

8-Fluoro-6-nitro-3,4-dihydroquinolin-2(1H)-one (5.9 g, 28.1 mmol) in borane-THF complex, 1M in THF (140 mL, 140 mmol) . This solution was heated to 60 ° C and stirred overnight. The mixture was cooled in an ice bath and quenched with methanol (30 mL). The quenched solution was concentrated, then dissolved in methanol and refluxed for 1 h. The solution was concentrated on silica gel and chromatographed using 5-30% ethyl acetate in hexane to afford desired 8-fluoro-6-nitro-1,2,3,4-tetrahydroquinoline (4.34 g, 22.12 mmol, 79% yield). ¹ H NMR (DMSO- d ₆ ) δ 7.77-7.71 (m, 1H), 7.73 (m, 1H), 7.31 (brs, 1H), 3.35-3.28 (m, 2H), 2.77 (t, J = 6.2 Hz) , 2H), 1.85-1.77 (m, 2H)

8-fluoro-1-(2-(1-methylpyrrolidin-2-yl)ethyl)-6-nitro -1,2,3,4-tetrahydroquinoline

Cool a solution of 8-fluoro-6-nitro-1,2,3,4-tetrahydroquinoline (500 mg, 2.55 mmol) in N,N -dimethylformamide (11 ml) with stirring. At 0 ° C, sodium hydride, 60% (326 mg, 8.16 mmol) was added and stirred vigorously. When the blistering subsided, 2-(2-chloroethyl)-1-methylpyrrolidinium chloride ( 938 mg, 5.10 mmol) was added, and the reaction mixture (dark red) was stirred at 90 ° C for 1 h. TLC analysis showed that the reaction mixture was complete. The mixture was cooled to room temperature, diluted with water and ethyl acetate (3x). The combined organic phases were washed with aq. EtOAc (EtOAc)EtOAc. The residue was chromatographed eluted EtOAc EtOAc (EtOAc) Ethyl)-6-nitro-1,2,3,4-tetrahydroquinoline (665 mg, 2.164 mmol, 85% yield). ¹ H NMR (DMSO- d ₆ ) δ 7.77 (dd, J = 15, 2.7 Hz, 1H), 7.71 (d, J = 2.4 Hz, 1H), 3.43 - 3.32 (m, 4H), 2.94 - 2.88 (m) , 1H), 2.78-2.73 (m, 2H), 2.19 (s, 3H), 2.06-1.97 (m, 2H), 1.91-1.83 (m, 4H); 1.64-1.56 (m, 4H)

8-fluoro-1-(2-(1-methylpyrrolidin-2-yl)ethyl)-1,2,3,4-tetrahydroquinolin-6-amine

8-Actyl-1-(2-(1-methylpyrrolidin-2-yl)ethyl)-6-nitro-1,2,3,4-tetrahydroquinoline (660 mg, stirred) 2.147 mmol) A solution of tetrahydrofuran (6 ml) and ethanol (6.00 ml), palladium-carbon, 10 wt% (229 mg, 0.215 mmol). The suspension was stirred under a hydrogen balloon pressure and monitored by TLC. After 4 h, the reaction was completed. The mixture was filtered through a pad of celite and washed with methanol. The filtrate was then concentrated and pumped dry under high vacuum. Residue (8-fluoro-1-(2-(1-methylpyrrolidin-2-yl)ethyl)-1,2,3,4-tetrahydroquinolin-6-amine (590 mg, 2.127 mmol, 99% yield)) was used directly in the subsequent reaction. ¹ H NMR (DMSO- d ₆ ) δ 6.16 (dd, J = 14.7, 2.4 Hz, 1H); 6.04 (m, 1H), 4.70 (brs, 1H), 2.99-2.93 (m, 3H), 2.88-2.82 (m, 2H), 2.57-2.53 (m, 2H), 2.24 (s, 3H), 2.15-2.05 (m, 2H); 1.93-1.87 (m, 2H) ), 1.69-1.60 (m, 4H), 1.44-1.35 (m, 2H)

N- (8-fluoro-1-(2-(1-methylpyrrolidin-2-yl)ethyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboxylate Yttrium imine

8-Fluoro-1-(2-(1-methylpyrrolidin-2-yl)ethyl)-1,2,3,4-tetrahydroquinolin-6-amine (580 mg, 2.091) Methyl) thiophene-2-carboquine thiocarboxylate hydrogen iodide (1193 mg, 4.18 mmol) solid. The resulting suspension was stirred at room temperature under argon overnight. The reaction mixture was quenched with water and sodium carbonate (sat) and extracted with dichloromethane (3x). The combined organic phases were dried, filtered and concentrated. The residue was then chromatographed in ethyl acetate, then 0-10% (2M NH3 in methanol) in dichloromethane chromatography to give the expectations N - (8- fluoro-l- (2- (1-methylpyrrole Pyridin-2-yl)ethyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboxyindoleimine amide (485 mg, 1.25 mmol, 60.0% yield). ¹ H NMR (DMSO- d ₆ ) δ 7.71 (d, J = 3 Hz, 1H), 7.57 (d, J = 4.5 Hz, 1H), 7.07 (dd, J = 4.8, 3.9 Hz, 1H), 6.44 (brs) , 2H), 6.39-6.34 (m, 2H), 3.07-3.02 (m, 4H), 2.95-2.89 (m, 1H), 2.69-2.65 (m, 2H), 2.21 (s, 3H), 2.03-1.99 (m, 2H), 1.94-1.87 (m, 2H), 1.76-1.74 (m, 2H), 1.63-1.59 (m, 2H), 1.46-1.40 (m, 2H)

N- (8-fluoro-1-(2-(1-methylpyrrolidin-2-yl)ethyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboxylate Yttrium imide amine dihydrogen

N- (8-fluoro-1-(2-(1-methylpyrrolidin-2-yl)ethyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2- Carboxylimine amide (485 mg, 1.255 mmol) was dissolved in MeOH (2.5 mL) and EtOAc (EtOAc) This solution was concentrated to give N- (8-fluoro-1-(2-(1-methylpyrrolidin-2-yl)ethyl)-1,2,3,4-tetrahydroquinolin-6- Thiophene-2-carboxyindoleimine decylamine hydrogen chloride 55 (575 mg, 1.251 mmol, 100% yield). ¹ H NMR (DMSO- d ₆ ) δ 11.44 (brs, 1H), 11.07 (m, 1H), 9.79 (brs, 1H), 8.82 (brs, 1H), 8.16m, 2H), 7.36 (t, J- 4.4 Hz, 1H), 7.10 (d, J = 13 Hz, 1H), 6.91 (brs, 1H), 4.19 (brs, 2H), 3.54-3.47 (m, 1H), 3.25-3.16 (m, 5H), 3.02 -2.96(m,1H), 2.77-2.73(m,5H), 2.29-2.22(m,2H),1.97-1.91(m,3H),1.85-1.81(m,2H),1.72-1.64(m, 1H). MS-EI+ (m/z, %) 386 (100, M+), 288 (55), 275 (82), 111 (68), 84 (64). EI+-HRMS calculated for C ₂₁ H ₂₇ FN ₄ S ⁺ (M+): 386.1938, observed: 386.1940.

Example 56 and Example 57

N- (1-(1-Methylpyrrolidin-3-yl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboxyindoleimide (56 and 57) :

The mirror image isomer mixture of 35 was separated using preparative chiral HPLC column chromatography to give 56 and 57 .

Column: Chiralpak AS-H (0.46 x 25cm) S/N 07-8314

Solvent: 40% isopropanol (0.1% DEA) / CO ₂ 100 bar

Wavelength: 220nm

Flow rate: 3mL/min.

The first eluted isomer was at 3.36 min ( 56 ): ESI-MS (m/z, %) 341.2 (MH ⁺ , 100); ESI-HRMS calculated for C ₁₉ H ₂₅ N ₄ S (MH ⁺ ), calculated: 341.1794; observed: 341.1798; chiral purity: 100%; chemical purity: 97.0%.

The second eluted isomer was at 4.17 min (57): ESI-MS (m/z, %) 341.2 (MH ⁺ , 100); ESI-HRMS calculated for C ₁₉ H ₂₄ N ₄ S (MH ⁺ ), calculated: 341.1794; observed: 341.1790; chiral purity: 99.86%; chemical purity: 97.1%

Example 58

4-(2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)piperidine-1-carboxylic acid tert-butyl ester 4,5-Dihydro-1H-benzo[b]azepine-2(3H)-one (2):

Compound 1 (1g, 6.793mmol), N--tert-butoxycarbonyl-4-piperidone (1.35g, 6.793mmol) and acetic acid (0.44mL, 6.793mmol) in 25mL 1,2- dichloroethane the mixture was cooled to 0 deg.] C, and is _{NaBH (OAc) 3 (2.16g,} 10.19mmol) process. The reaction was brought to room temperature and stirred for 2 days. This solution was diluted with a 3N NaOH solution (125 mL) and ethyl acetate (200 mL). The organic layer was washed with brine (50mL), dried (Na ₂ SO ₄₎ and concentrated. The crude product was applied to a silica gel using 5% ethyl acetate /hexane. The sample was concentrated and dried to give a colorless viscous liquid, Compound 2 (2.12 g, 94%). ¹ H NMR (CDCl ₃ ) δ 7.12-7.08 (m, 2H), 6.93 (d, J = 7.8 Hz, 1H), 6.83 (t, J = 14.7 Hz, 1H), 4.16 - 4.13 (m, 2H), 3.42 (tt, J=7.2, 22.2 Hz, 1H), 2.98 (brs, 2H), 2.85-2.75 (m, 4H), 1.88 (d, J = 12.0 Hz, 2H), 1.73-1.60 (m, 6H) , 1.47 (s, 9H); MS-ESI (m/z, %): 331 (MH ⁺ , 17), 275 (100)

4-(7-Bromo-2,3,4,5-tetrahydro-1H-benzo[b]hydroindol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (3):

A solution of compound 2 (1.004 g, 3.026 mmol) in EtOAc (EtOAc)EtOAc. The reaction mixture was stirred at 0 ° C for 1.5 h. The reaction was diluted in H ₂ O (100 mL) and extracted with ethyl acetate (200mL). The organic layer was washed with brine and dried (Na ₂ SO _4). The crude product was purified by flash chromatography on silica using 5% EtOAc / hexanes to give a white solid, compound 3 (1.26,101%). ¹ H NMR (CDCl ₃ ) δ 7.21-7.15 (m, 2H), 6.78 (d, J = 8.4 Hz, 1H), 4.15 - 4.12 (m, 2H), 3.35 (tt, J = 7.2, 18.3 Hz, 1H) ), 2.95 (brs, 2H), 2.90-2.69 (m, 4H), 1.84 (d, J = 12.3, 2H), 1.71-1.62 (m, 6H), 1.46 (s, 9H); MS-ESI (m) /z, %): 411 (MH ⁺ , 15), 409 (M ⁺ , 15), 355 (96), 353 (100)

4-(7-Amino-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)piperidine-1-carboxylic acid tert-butyl ester (4):

The _{Pd 2 (dba) 3 (0.107g} , 0.1172mmol) in anhydrous THF (5mL) of the solution to PtBu ₃ (10% in hexanes, 1.42mL, 0.4688mmol) process. This mixture was treated with compound 3 (0.9594 g, 2.344 mmol) in dry THF (15 mL) and LiHMDS (4.69 <RTIgt; This solution was stirred at 100 ° C for 3 hours. This solution was quenched with 1 M TBAF in THF (5 mL) and stirred for 20 min. The reaction was diluted with 3N NaOH solution (50 mL) andEtOAcEtOAc The organic layer was dried (Na ₂ SO ₄₎ and concentrated. The crude product was applied to flash chromatography on silica, using 2.5% 2M NH ₃ in methanol / CH ₂ Cl _2, to give a dark brown foam, Compound 4 (0.691g, 85%). ¹ H NMR (CDCl ₃ ) δ 6.79 (d, J = 5.1 Hz, 1H), 6.51-6.44 (m, 2H), 4.06-4.03 (m, 2H), 3.56-3.51 (m, 1H), 3.28 (tt , J=7.2, 21.3 Hz, 1H), 2.92-2.77 (m, 4H), 2.68-2.64 (m, 2H), 1.82 (d, J = 11.1 Hz, 2H), 1.66-1.40 (m, 7H), 1.36 (s, 9H).

4-(7-(thiophene-2-carboxyindolinamine)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)piperidine-1-carboxylic acid Third butyl ester (5):

A solution of compound 4 (0.6586 g, 1.906 mmol) in dry ethyl acetate (20 mL) eluted with methyl thiophene-2-carbomine thiocarboxylate hydrogen iodide (1.087 g, 3.812 mmol) at room temperature Stir for 3 hours. The mixture was diluted with a saturated aqueous solution of sodium bicarbonate (50 mL) and evaporated. The organic layer was washed with brine (20mL) and dried (Na ₂ SO _4). The concentrated crude product was applied to the flash chromatography on silica, using _{2.5-5% MeOH / CH 2 Cl 2} , to give a brown foam, compound 5 (0.42g, 48%). ¹ H NMR (CDCl ₃ ) δ 7.42-7.40 (m, 2H), 7.08-7.05 (t, J = 9.0 Hz, 1H), 6.92 (d, J = 8.1 Hz, 1H), 6.77-6.73 (m, 2H) ), 4.3-4.09 (m, 2H), 3.37 (tt, J = 7.2, 21.9 Hz, 1H), 2.95-2.71 (m, 6H), 1.87 (d, J = 12.9 Hz, 2H), 1.77-1.53 ( m,7H), 1.47 (s, 9H); MS-ESI (m/z, %): 457 (MH ⁺ , 14), 455 (M ⁺ , 100), 219 (18)

N-(1-(piperidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-yl)thiophene-2-carboxyindoleimine amide ( 58):

A solution of compound 5 (0.4199 g, 0.9236 mmol) in EtOAc (EtOAc) The reaction was taken to room temperature, concentrated and concentrated under reduced vacuum. The product was filtered and recrystallized to afford one-yellow dihydrochloride salt, compound 58 (0.323 g, 79%). ¹ H NMR (CDCl ₃ ) δ 7.69 (d, J = 3.3 Hz, 1H), 7.57 (d, J = 4.2 Hz, 1H), 7.07 (t, J = 8.7, 1H), 6.90 (d, J = 9.0 Hz, 1H), 6.59 (d, J = 6.9 Hz, 2H), 6.36-6.20 (m, 2H), 3.42-3.20 (m, 4H), 3.03-2.91 (m, 4H), 2.64-2.57 (m, 4H), 1.78 (d, J = 11.4 Hz, 2H), 1.57-1.54 (m, 6H); MS-ESI (m/z, %): 355 (MH ⁺ , 72), 272 (100), 219 ( 48); ESI-HRMS calcd for C ₂₀ H ₂₇ N ₄ S (MH ⁺ ): Calculated: 355.1950, observed: 355.1968.

Example 59

1-(3-chloropropyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one

A stirred solution of 6-nitro-3,4-dihydroquinolin-2(1H)-one (5 g, 26.0 mmol) in DMF (100 mL). 78mmol). The mixture was stirred until bubbling ceased and 1-chloro-3-iodopropane (8.23 mL, 78 mmol) was added. The reaction was maintained in an ice bath and allowed to slowly warm to room temperature. Then stir overnight. The reaction mixture was diluted with water and extracted with EtOAc (EtOAc). The combined organic phases were washed with a 1:1 mixture of brine and water (3x) and brine (1x). The organic phase is dried, filtered and concentrated and purified eluting elut elut 2(1H)-ketone (5.22 g, 19.43 mmol, 74.7% yield).

1-(3-(Dimethylamino)propyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one

1-(3-Chloropropyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (5.22 g, 19.43 mmol), potassium iodide (3.22 g, 19.43 mmol) And a suspension of potassium carbonate (16.11 g, 117 mmol) in acetonitrile (100 ml), dimethylamine hydrogen chloride (6.34 g, 78 mmol). The resulting mixture was stirred at 50 ° C overnight. The mixture was cooled to room temperature, diluted with water and extracted with dichloromethane (3x). The combined organics were dried, filtered and concentrated and purified eluting eluting eluting ¹ H NMR (DMSO- d ₆ ) δ 8.14-8.10 (m, 2H), 7.37 (d, J = 9.6 Hz, 1H), 3.94 (t, J = 7.5 Hz, 2H), 3.00 (t, J = 7.5) Hz, 2H), 2.62 (t, J = 7.5 Hz, 1H), 2.27 (t, J = 7 Hz, 2H), 2.13 (s, 6H), 1.66 (quint, J = 7.5 Hz, 1H). ESI-MS (m/z, %) 278 (MH+, 100)

N,N -Dimethyl-3-(6-nitro-3,4-dihydroquinolin-1(2H)-yl)propan-1-amine

1-(3-(Dimethylamino)propyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (4.23 g, 15.25 mmol) was conjugated to borane tetrahydrofuran 1 M (76 ml, 76 mmol) was stirred at 60 ° C overnight. The reaction mixture was then cooled to 0 ° C and quenched with the addition of methanol. The resulting suspension was concentrated and stirred in EtOAc (EtOAc) To this solution, a solution of sodium hydroxide (6.10 g, 153 mmol) was added to a small amount of water. The resulting mixture was refluxed at 90 °C. After 1 h, no free product was observed, only the product borane complex. The solution was diluted with water and acidified with cone. HCl and reflux at 90. After 1 h, TLC analysis showed the free product, and the borane-free complex. This mixture was neutralized by addition of NaOH (3N) and extracted with dichloromethane (3×). ¹ H NMR (DMSO- d ₆ ) δ 7.87 (dd, J = 9.3, 3 Hz, 1H), 7.77 (d, J = 3 Hz, 1H), 6.68 (d, J = 9.6 Hz, 1H), 3.43 - 3.38 ( m, 4H), 2.74 (t, J = 6 Hz, 2H), 2.23 (t, J = 6.5 Hz, 2H), 2.13 (s, 6H), 1.85 (quint, J = 6 Hz, 2H), 1.68 (quint, J = 7 Hz, 2H). ESI-MS (m/z, %) 264 (MH+, 100)

1-(3-(Dimethylamino)propyl)-1,2,3,4-tetrahydroquinolin-6-amine

A pair of stirring N, N - dimethyl-3- (6-nitro-3,4-dihydro-quinoline -1 (2H) - yl) propan-1-amine (600mg, 2.278mmol) in methanol (12 ml) solution, Raney nickel (60 mg, 2.278 mmol) was added, followed by hydrazine hydrate (1.108 ml, 22.78 mmol). The resulting mixture was stirred at 60 ° C and the initial material consumption was monitored by TLC. The reaction mixture was then filtered through celite and concentrated. The residue was dissolved in dichloromethane, dried, filtered and concentrated to give a dark oil. ¹ H NMR (DMSO- d ₆ ) δ 6.37-6.34 (m, 1H), 6.30-6.26 (m, 1H), 6.22-6.20 (m, 1H), 4.17 (brs, 2H), 3.12-3.03 (m, 4H), 2.55 (t, J = 6.45 Hz, 2H), 2.20 (t, J = 6.9 Hz, 2H), 2.11 (s, 6H), 1.79 (quint, J = 6 Hz, 2H), 1.56 (quint, J =7.12 Hz, 2H). ESI-MS (m/z, %) 234 (MH+, 100), 161 (60)

N -(1-(3-(Dimethylamino)propyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiazide Phen-2-carboxyindole

a solution of 1-(3-(dimethylamino)propyl)-1,2,3,4-tetrahydroquinolin-6-amine (490 mg, 2.100 mmol) in ethanol (30 mL) Methylthiophene-2-carboquinone thiocarboxylate hydrogen iodide (1198 mg, 4.20 mmol) was added. The reaction mixture was stirred at room temperature overnight. This mixture was then diluted with water and aqueous sodium carbonate (sat) and then extracted with dichloromethane (3x). The combined organic phases were dried, filtered and concentrated. The crude product was chromatographed on silica gel, using ethyl acetate as solvent, and then using 5-10% (2M NH3 in methanol) in dichloromethane to give 1M HCl ether solution to give the desired N- (1-(3) - (dimethylamino) propyl) -1,2,3,4-tetrahydro-quinolin-6-yl) thiophene-2-carboxamide (PEI) Amides 59 (613mg, 1.790mmol, 85% yield) . ¹ H NMR (DMSO- d ₆ ) δ 7.67 (d, J = 3 Hz, 1H), 7.55 (d, J = 5.1 Hz, 1H), 7.07 (dd, J = 5.1, 3 Hz, 1H), 6.55 (m, 2H), 6.48 (m, 1H), 6.31 (brs, 2H), 3.24 - 3.17 (m, 4H), 2.66 (t, J = 6.3 Hz, 2H), 2.25 (t, J = 6.9 Hz, 2H), 1.88-1.82 (m, 2H), 1.67-1.60 (m, 2H). ESI-MS (m/z, %) 343 (MH+, 89), 258 (100), 135 (48), 127 (60). ESI-HRMS calculated for C19H27N4S (MH+), calc.: 343. 1963, observed: 343.195. HPLC purity: 97%.

Example 60

1-(6-Bromo-3,4-dihydroquinolin-1(2H)-yl)-2-chloroethanone (1): See Example 51 for complete experimental details and spectral data. 6-Bromo-1-(2-chloroethyl)-1,2,3,4-tetrahydroquinoline (2):

A round bottom flask was charged with 1-(6-bromo-3,4-dihydroquinolin-1(2H)-yl)-2-chloroethanone (Compound 1 , 0.546 g, 1.892 mmol). - THF complex (1M in THF, 18.9 mL, 18.9 mmol, 10 eq.), and the mixture was stirred at room temperature overnight. After cooling to 0 ° C, the reaction was quenched with methanol (5 mL) and stirred at 0 ° C for 10 min. The mixture was concentrated under reduced pressure, and purified directly on silica eluting with 10% ethyl acetate / 90% hexane to produce sticky residue, 2 (0.519g, 100%) . ¹ H-NMR (CDCl ₃ ) δ 7.11 (dd, 1H, J = 8.7, 2.4 Hz), 7.08-7.04 (m, 1H), 6.42 (d, 1H, J = 8.7), 3.64-3.56 (m, 4H) ), 3.35 (t, 2H, J = 5.6 Hz), 2.73 (t, 2H, J = 6.3 Hz), 1.97-1.89 (m, 2H). MS (ESI+): 274/276 (MH ⁺ , 100)

6-Bromo-1-(2-iodoethyl)-1,2,3,4-tetrahydroquinoline (3):

6-Bromo-1-(2-chloroethyl)-1,2,3,4-tetrahydroquinoline (Compound 2 , 1.80 g, 6.56 mmol) and sodium iodide (9.83 g, 65.6 mmol) in acetone A suspension of (50 mL) was heated to reflux for 2 days at which time TLC analysis showed residue starting material 2 . At this point, another portion of sodium iodide (19.66 g, 132.0 mmol) was added and the suspension was refluxed for 5 days. The mixture was cooled to room temperature, filtered through a pad of celite and concentrated to yield a yellow solid. The solid was taken into a mixture of ethyl acetate / hexane (150 mL). The filtrate was concentrated to give a yellow oil, 3 ( 2.19 g, 91%). ¹ H-NMR (CDCl ₃ ) δ 7.12 (dd, 1H, J = 8.7, 2.5 Hz), 7.09-7.04 (m, 1H), 6.42 (d, 1H, J = 8.7), 3.65-3.60 (m, 2H) ), 3.33 (t, 2H, J = 5.6 Hz), 3.25-3.19 (m, 2H), 2.72 (t, 2H, J = 6.3 Hz), 1.98-1.90 (m, 2H). MS (ESI+): 366/368 (MH ⁺ , 100)

2-(6-Bromo-3,4-dihydroquinolin-1(2H)-yl)-N-ethylethylamine (4):

a solution of 6-bromo-1-(2-iodoethyl)-1,2,3,4-tetrahydroquinoline (Compound 3 , 100 mg, 0.273 mmol) in acetonitrile (4.75 mL) and water (0.25 mL) It was treated with potassium carbonate (0.378 g, 2.73 mmol) and ethylamine hydrogen chloride (0.223 g, 2.73 mmol) in a 20 mL pressure vessel equipped with a stir bar, and the sealed vessel was stirred at 70 ° C overnight. After 18 hours, the mixture between CH ₂ Cl ₂ (50mL) and water (10mL) delamination and transferred to a separatory funnel. The organic layer was separated and the aqueous layer was further extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate The residue was purified on silica, to 7.5% 2M NH ₃ in methanol /92.5% dichloromethane eluent to yield a yellow oil / residue, 4 (55mg, 71.1%) . ¹ H-NMR (CDCl ₃ ) δ 7.09 (dd, 1H, J = 8.7, 2.4 Hz), 7.06-7.01 (m, 1H), 6.51 (d, 1H, J = 8.7), 3.36 (t, 2H, J) = 6.8 Hz), 3.29 (t, 2H, J = 5.5 Hz), 2.82 (t, 2H, J = 6.8 Hz), 2.80 - 2.65 (2 x m, 4H), 1.96-1.88 (m, 2H), 1.11 ( t, 3H, J = 7.1 Hz)

T-butyl 2-(6-bromo-3,4-dihydroquinolin-1(2H)-yl)ethyl(ethyl)aminecarboxylate (5):

2-(6-Bromo-3,4-dihydroquinolin-1(2H)-yl)-N-ethylethylamine (Compound 4 , 0.250 g, 0.883 mmol) in anhydrous dioxane (15 mL) The solution was treated with triethylamine (0.248 mL, 1. 765 mmol) and di-t-butyldicarbonate (0.202 g, 0.927 mmol). The mixture was concentrated to a residue, and purified directly on silica with 10% ethyl acetate / hexanes to 90% to give a colorless oil, 5 (0.280g, 83%) . ¹ H-NMR (CDCl ₃ ) δ 7.09 (dd, 1H, J = 8.7, 2.3 Hz), 7.03 (br s, 1H), 6.50 (d, 1H, J = 8.7), 3.48-3.11 (m, 8H) , 2.70 (t, 2H, J = 6.3 Hz), 2.05-1.87 (m, 2H), 1.47 (s, 9H), 1.10 (br s, 3H). MS (ESI+): 383/385 (MH ⁺ , 38), 327/329 (100)

2-(6-Amino-3,4-dihydroquinolin-1(2H)-yl)ethyl(ethyl)aminecarboxylic acid tert- butyl ester (6):

A suspension of bis(dibenzylideneacetone)dipalladium(0) (66 mg, 0.072 mmol) in dry THF (3 mL), EtOAc (EtOAc) The mixture was stirred at room temperature for 5 minutes. Addition of tert - butyl 2-(6-bromo-3,4-dihydroquinolin-1(2H)-yl)ethyl(ethyl)carbamate (Compound 5 , 0.275 g, 0.717 mmol) in THF A solution of (7 mL) was added lithium bis(trimethyldecyloxy)guanamine (1M in THF, 1.435 mL, 1.435 mmol). The mixture was cooled to room temperature and treated with TBAF (1M in THF, 4 mL, 4 mmol) for 30 min. The mixture was partitioned between water (10 mL) and ethyl acetate (100 mL) and transferred to a sep. funnel. The aqueous layer (pH = 10) was further extracted with ethyl acetate, and the combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to give a dark brown residue. On silica eluting with 2.5% 2M NH ₃ in methanol /97.5% dichloromethane elution to produce a brown residue, 6 (171mg, 74.6%) . ¹ H-NMR ((DMSO-d ₆ ) δ 6.42 (d, 1H, J = 8.5 Hz), 6.31-6.26 (m, 1H), 6.22 (br s, 1H), 4.20 (br s, 2H), 3.26 -3.08 (m, 8H), 2.55 (t, 2H, J = 6.3 Hz), 1.82-1.74 (m, 2H), 1.41 (s, 9H), 1.02 (t, 3H, J = 7.0 Hz). ESI+): 320 (MH ⁺ , 90), 264 (100)

Ethyl (2-(6-(thiophene-2-carboxyindolinamine)-3,4-dihydroquinolin-1(2H)-yl)ethyl)aminecarboxylic acid tert- butyl ester (8):

Ternyl butyl 2-(6-amino-3,4-dihydroquinolin-1(2H)-yl)ethyl(ethyl)amine formate (Compound 6 , 165 mg, 0.517 mmol) in anhydrous EtOH (10mL) of solution of methyl thiophene-2-acyl imine carbon thionoester hydrogen iodide (compound 7, 295mg, 1.033mmol) part of the process, and the mixture was stirred at room temperature for 20 hours. This mixture CH ₂ Cl ₂ (100mL) and partitioned between saturated Na ₂ CO ₃ (20mL), and transferred to a separatory funnel. The organic layer was separated, and the aqueous layer (pH = 9) was further extracted with CH ₂ Cl ₂ . The combined organic layers were washed with brine, dried over magnesium sulfate On silica eluting with 1% methanol / 99% dichloromethane as eluent, then to 2.5% 2M NH ₃ in methanol /97.5% generated eluting methylene chloride to give yellow - orange solid, 8 (120mg, 54.2%) . ¹ H-NMR (DMSO-d ₆ ) δ 7.69 (d, 1H, J = 3.2 Hz), 7.58 (d, 1H, J = 5.0 Hz), 7.08 (dd, 1H, J = 5.0, 3.7 Hz), 6.68 -6.59 (m, 1H), 6.59-6.47 (m, 2H), 6.50-6.20 (br s, 2H), 3.33-3.16 (m, 8H), 2.66 (t, 2H, J = 6.2 Hz), 1.91 1.79 (m, 2H), 1.41 (s, 9H), 1.04 (t, 3H, J = 7.0 Hz). MS (ESI+): 429 (MH ⁺ , 100)

N- (1-(2-(ethylamino)ethyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboximine amide (9):

Ethyl (2-(6-(thiophene-2-carboxyindoleamine)-3,4-dihydroquinolin-1(2H)-yl)ethyl)aminecarboxylic acid tert- butyl ester (Compound 8) A solution of <RTI ID=0.0></RTI></RTI><RTIID=0.0></RTI></RTI><RTIgt;</RTI><RTIgt; After cooling to room temperature, the solution was concentrated and briefly dried under high vacuum pump. The residue was directly purified on silica, to 10% 2M NH ₃ in methanol / 90% dichloromethane eluent to yield a yellow solid, 9 (78mg, 88%) . ¹ H-NMR (DMSO-d ₆ ) δ 7.66 (d, 1H, J = 3.0 Hz), 7.54 (dd, 1H, J = 5.0, 0.9 Hz), 7.06 (dd, 1H, J = 5.0, 3.7 Hz) , 6.59-6.52 (m, 2H), 6.47 (br s, 1H), 6.21 (br s, 2H), 3.32-3.20 (m, 4H), 2.70-2.64 (m, 4H), 2.56 (q, 2H, J = 7.1 Hz), 1.88-1.80 (m, 2H), 1.04 (t, 3H, J = 7.0 Hz). MS (ESI +): 329 ( MH +, 100), 258 (100); ESI-HRMS calcd for _{C 18 H 25 N 4 S (} MH +): 329.1794; observed: 329.1798.

Example 61

6-Bromo-1-(2-iodoethyl)-1,2,3,4-tetrahydroquinoline (1):

See 60 of Example complete experimental details and spectral data

N- (2-(6-Bromo-3,4-dihydroquinolin-1(2H)-yl)ethyl)propan-2-amine (2):

a solution of 6-bromo-1-(2-iodoethyl)-1,2,3,4-tetrahydroquinoline (Compound 1 , 0.400 g, 1.093 mmol) in acetonitrile (19 mL) and water (1 mL) The vessel was treated with potassium carbonate (0.755 g, 5.46 mmol) and isopropylamine (0.646 g, 10.93 mmol) and stirred at 75 ° C overnight. After 24 hours, the mixture was Room in CH ₂ Cl ₂ (50mL) and water (10mL) delamination and transferred to a separatory funnel. The organic layer was separated and the aqueous layer was taken (pH = 12); The combined organic layers were washed with brine, dried over sodium sulfate On silica eluting with 5% 2M NH ₃ in methanol / 95% dichloromethane as eluent, to produce a slightly yellow oil, 2 (270mg, 83%) . ¹ H-NMR (DMSO-d ₆ ) δ 7.06 (dd, 1H, J = 8.8, 2.5 Hz), 6.99 (d, 1H, J = 2.5 Hz), 6.52 (d, 1H, J = 8.8), 3.31 3.20 (m, 4H), 2.78-2.67 (m, 1H), 2.67-2.59 (m, 4H), 1.84-1.76 (m, 2H), 0.96 (d, 6H, J = 6.2 Hz). MS (ESI+): 297/299 (MH ⁺ , 10), 238/240 (20), 159 (100)

2-(6-Bromo-3,4-dihydroquinolin-1(2H)-yl)ethyl(isopropyl)-carbamic acid tert-butyl ester (3):

N-(2-(6-Bromo-3,4-dihydroquinolin-1(2H)-yl)ethyl)propan-2-amine (Compound 2 , 0.140 g, 0.471 mmol) in anhydrous dioxane (10 mL) of the solution, triethyl amine (0.132mL, 0.942mmol) and two third-butyl dicarbonate (0.108g, 0.495mmol) process, and the resulting mixture was stirred overnight at the room temperature. The mixture was concentrated and the residue was directly purified on silica with 10% ethyl acetate / hexanes to 90% to give a colorless oil, 3 (0.150g, 80%) . ¹ H-NMR (CDCl ₃ ) δ 7.09 (dd, 1H, J = 8.7, 2.0 Hz), 7.05-7.00 (m, 1H), 6.55 (d, 1H, J = 8.7), 4.50-4.00 (br m, 1H), 3.42-3.27 (m, 4H), 3.24 - 3.11 (m, 2H), 2.70 (t, 2H, J = 6.2 Hz), 1.97-1.86 (m, 2H), 1.53-1.51 (2 xs, 9H) ), 1.13 (d, 6H, J = 6.8 Hz). MS (ESI+): 397/399 (MH ⁺ , 80), 341/343 (100)

2-(6-Amino-3,4-dihydroquinolin-1(2H)-yl)ethyl(isopropyl)-carbamic acid tert- butyl ester (4):

A suspension of bis(dibenzylideneacetone)dipalladium(0) (35 mg, 0.038 mmol in anhydrous THF (3 mL), EtOAc (3% EtOAc) process, and the mixture was stirred at room temperature for 5 minutes was added a third-butyl-2- (6-bromo-3,4-dihydro-quinoline -1 (2H) - yl) ethyl (isopropyl) amine A solution of the formic acid ester (Compound 3 , 0.150 g, 0.378 mmol) in THF (7 mL), EtOAc (EtOAc (EtOAc) Heated for 3 hours at 90 ° C in a sealed vial. The mixture was cooled to room temperature and treated with TBAF (1M in THF, 3 mL, 3 mmol) for 30 min. The mixture was taken in water (10 mL) and ethyl acetate (100 mL) The layers were separated, transferred to a separatory funnel, and the organic layer was separated. The aqueous layer (pH = 10) was further extracted with ethyl acetate, and the combined organic layers were washed with brine and dried over sodium sulfate. , filtered and concentrated to give a dark brown - red residue was purified on silica, to 2.5% 2M NH ₃ stripping, to produce a dark brown residue in methanol /97.5% dichloromethane, 4 (85mg, 67.5%) 1 H-NMR (DMSO-d ₆ ) δ 6.44 (d, 1H, J = 8.0 Hz), 6.28 (dd, 1H, J = 8.3, 2.1 Hz) , 6.24-6.18(m,1H),4.33-3.91(br m+br s,3H),3.24-3.04(m,6H), 2.60-2.50(m,2H),1.85-1.74(m,2H), 1.44 (s, 9H), 1.07 (d, 6H, J = 6.8 Hz). MS (ESI+): 334 (MH ⁺ , 100)

Isopropyl (2- (6- (thiophene-2-carboxamide (PEI) Amides) -3,4-dihydro - quinoline -1 (2H) - yl) ethyl) amine acid tert-butyl ester (6 ):

3-(6-Amino-3,4-dihydroquinolin-1(2H)-yl)ethyl(isopropyl)carbamic acid tert -butyl ester (Compound 4 , 85 mg, 0.255 mmol) in absolute ethanol A solution of (10 mL) was treated with methyl thiophene-2-carbomine thiocarboxylate hydrogen iodide (Compound 5 , 127 mg, 0.446 mmol), and the mixture was stirred at room temperature for 18 hr. TLC analysis showed that about 80% of the starting material was consumed, and another portion of methylthiophene-2-carboquine thiocarboxylate hydrogen iodide (Compound 5 , 18.1 mg, 0.063 mmol) was added and the mixture was placed in the chamber. Stir for 4 hours. This mixture CH ₂ Cl ₂ (100mL) and between saturated Na ₂ CO ₃ (20mL) delamination and transferred to a separatory funnel. The organic layer was separated, and the aqueous layer (pH = 9) was further extracted with CH ₂ Cl ₂ . The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated. On silica eluting with 1% methanol / 99% dichloromethane followed by 2.5% 2M NH ₃ in methanol /97.5% dichloromethane elution to produce a yellow solid, 6 (54mg, 47.9%) . ¹ H-NMR (DMSO-d ₆ ) δ 7.70 (d, 1H, J = 3.4 Hz), 7.59 (d, 1H, J = 5.0 Hz), 7.09 (dd, 1H, J = 5.0, 3.6 Hz), 6.71 -6.51 (2 xm, 3H), 6.51-6.28 (br s, 2H), 4.29-3.94 (br m, 1H), 3.43-3.18 (2 xm, 6H), 2.66 (t, 2H, J = 5.8 Hz) , 1.91-1.80 (m, 2H), 1.46 (s, 9H), 1.11 (d, 6H, J = 6.8 Hz). MS (ESI+): 443 (MH ⁺ , 100)

N- (1-(2-(Isopropylamino)ethyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboximine amide (61):

Isopropyl (2- (6- (thiophene-2-carboxamide (PEI) Amides) -3,4-dihydro - quinoline -1 (2H) - yl) ethyl) amine acid tert-butyl ester ( Compound 6 , 50 mg, 0.113 mmol) EtOAc (EtOAc)EtOAc. This solution was concentrated and briefly dried by high vacuum pumping. The residue was placed in 7.5% 2M NH ₃ in methanol /92.5% dichloromethane (5 mL), and concentrated, then purified directly on silica in 7.5% 2M NH ₃ in methanol /92.5% dichloromethane eluent to yield Yellow solid, 61 (40 mg, quantitative). ¹ H-NMR (DMSO-d ₆ ) δ 7.66 (d, 1H, J = 3.1 Hz), 7.54 (d, 1H, J = 5.1 Hz), 7.06 (dd, 1H, J = 5.0, 3.7 Hz), 6.61 -6.50 (m, 2H), 6.47 (br s, 1H), 6.21 (br s, 2H), 3.30-3.18 (m, 4H), 2.79-2.70 (m, 1H), 2.70-2.61 (m, 4H) , 1.88-1.80 (m, 2H), 0.97 (d, 6H, J = 6.2 Hz). MS (ESI +): 343 ( MH +, 100); ESI-HRMS calcd for _{C 19 H 27 N 4 S (} MH +): 343.1950; observed: 343.1953.

Example 62

6-Bromo-1-(2-iodoethyl)-1,2,3,4-tetrahydroquinoline (1):

See 60 of Example complete experimental details and spectral data

2-((2-(6-Bromo-3,4-dihydroquinolin-1(2H)-yl)ethyl)(methyl)amino)ethanol (2):

a solution of 6-bromo-1-(2-iodoethyl)-1,2,3,4-tetrahydroquinoline (Compound 1 , 0.475 g, 1.298 mmol) in acetonitrile (19 mL) and water (1 mL) Treated with potassium carbonate (1.793 g, 12.98 mmol) and 2-(methylamino)ethanol (0.975 g, 12.98 mmol) in a 50 mL pressure vessel equipped with a stir bar, and the sealed container was stirred at 80 ° C. night. After 18 hours, the mixture was Room in CH ₂ Cl ₂ (100 mL) and water (20mL) delamination and transferred to a separatory funnel. The organic layer was separated and the aqueous layer was taken (pH = 12); The combined organic layers were washed with brine, dried over sodium sulfate On silica eluting with 5% 2M NH ₃ in methanol / 95% dichloromethane as eluent, to produce a slightly yellow oil, 2 (341mg, 84%) . ¹ H-NMR (DMSO-d ₆ ) δ 7.06 (dd, 1H, J = 8.8, 2.5 Hz), 6.99 (d, 1H, J = 2.4 Hz), 6.48 (d, 1H, J = 8.8), 4.34 ( t,1H,J=5.3Hz), 3.44(q,2H,J=6.2Hz),3.32-3.25(m,4H),2.64(t,2H,J=6.2Hz),2.47-2.41(m,4H ), 2.23 (s, 3H), 1.83-1.76 (m, 2H). MS (ESI+): 313/315 (MH ⁺ , 100).

2-((2-(6-Amino-3,4-dihydroquinolin-1(2H)-yl)ethyl)(methyl)amino)ethanol (3):

A suspension of bis(dibenzylideneacetone)dipalladium(0) (48 mg, 0.053 mmol) in dry THF (3 mL), EtOAc (3% EtOAc) The mixture was stirred at room temperature for 5 minutes. Add 2-((2-(6-bromo-3,4-dihydroquinolin-1(2H)-yl)ethyl)(methyl)amino)ethanol (Compound 2 , 0.165 g, 0.527 mmol) A solution of THF (7 mL) was added EtOAc (EtOAc &lt;RTI ID=0.0&gt;&gt; The mixture was cooled to room temperature, then quenched to 0&lt;0&gt;C with 3N aq. HCl (1. 5 mL) and stirred slowly for 30 min. The mixture was diluted with ethyl acetate, basified to pH~10 with 1N aq NaOH and transferred to a sep. funnel. The organic layer was separated and the aqueous layer was purified eluting with EtOAc (EtOAc) On silica eluting with 7.5% 2M NH ₃ in methanol /92.5% dichloromethane elution to produce an orange - red residue, 3 (57mg, 43.4%) . ¹ H-NMR (DMSO-d ₆ ) δ 6.36-6.27 (m, 2H), 6.21 (br s, 1H), 4.31 (t, 1H, J = 5.4 Hz, exch. D ₂ O), 4.18 (br s , 2H, exch.D ₂ O), 3.44 (q, 2H, J = 6.3 Hz), 3.18 (t, 2H, J = 7.3 Hz), 3.10 (t, 2H, J = 5.3 Hz), 2.56-2.40 ( 2 xm, 6H), 2.22 (s, 3H), 1.84-1.72 (m, 2H). MS (ESI+): 250 (MH ⁺ , 100).

N- (1-(2-(2-hydroxyethyl)(methyl)amino)ethyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboxyindole Iminoguanamine (62):

2-((2-(6-Amino-3,4-dihydroquinolin-1(2H)-yl)ethyl)(methyl)amino)ethanol (Compound 3, 52 mg, 0.209 mmol) anhydrous EtOH (10mL) of solution of methyl thiophene-2-acyl imine carbon thionoester hydrogen iodide (compound 4, 119mg, 0.417mmol) part of the process, and the mixture was stirred at room temperature for 20 hours. The solution was concentrated and the residue was placed in a 7.5% 2M NH ₃ in methanol /92.5% dichloromethane (5 mL), and concentrated, then purified directly on silica in 7.5% 2M NH ₃ in methanol /92.5% dichloro Methane was eluted to give a yellow solid, 62 (44 mg, 58.9%). ¹ H-NMR (DMSO-d ₆ ) δ 7.67 (d, 1H, J = 3.0 Hz), 7.55 (dd, 1H, J = 5.0, 0.9 Hz), 7.07 (dd, 1H, J = 5.0, 3.7 Hz) , 6.60-6.51 (m, 2H), 6.48 (br s, 1H), 6.29 (br s, 2H, exch. D ₂ O), 4.34 (t, 1H, J = 5.3 Hz, exch. D ₂ O), 3.46 (q, 2H, J = 6.2 Hz), 3.32-3.22 (m, 4H), 2.65 (t, 2H, J = 6.2 Hz), 2.50-2.44 (m, 4H), 2.25 (s, 3H), 1.88 -1.80 (m, 2H). MS (ESI+): 359 (MH ⁺ , 100). ESI-HRMS calculated for C ₁₉ H ₂₇ N ₄ OS (MH ⁺ ): 359.1900; observed: 359.1908.

Example 63

N,N -Dimethyl-3-(6-nitro-3,4-dihydroquinolin-1(2H)-yl)propan-1-amine:

See details of Example 59

Phenylmethyl (3-(6-nitro-3,4-dihydroquinolin-1(2H)-yl)propyl)aminecarboxylate:

N,N -Dimethyl-3-(6-nitro-3,4-dihydroquinolin-1(2H)-yl)propan-1-amine (1 g, 3.80 mmol) in a stirring A solution of methyl chloride (20 ml) was added phenyl chloroformate (0.715 ml, 5.70 mmol). The resulting solution was stirred at room temperature overnight. The reaction mixture was then diluted with water and extracted with dichloromethane (3×). The combined organics were dried, filtered and concentrated then purified eluting elut elut 2H)-Phenyl)propyl) phenyl carbamate (1.02 g, 2.76 mmol, 72.7% yield). ¹ H NMR (DMSO- d ₆ ) δ 7.88 (t, J = 7 Hz, 1H), 7.78 (s, 1H), 7.37 (t, J = 7 Hz, 2H), 7.20 (t, J = 7 Hz, 1H), 7.12-7.06 (m, 2H), 6.70 (d, J = 9 Hz, 1H), 3.50-3.33 (m, 6H), 3.06, 2.93 (2s, 3H), 2.76-2.71 (m, 2H), 1.92-1.81 (m, 4H). ESI-MS (m/z, %) 370 (MH+, 100)

Phenyl 3-(6-Amino-3,4-dihydroquinolin-1(2H)-yl)propyl(methyl)aminecarboxylate:

Phenylmethyl (3-(6-nitro-3,4-dihydroquinolin-1(2H)-yl)propyl)carbamate (1.02 g, 2.76 mmol) in THF A solution of (15.00 ml) and ethanol (15 ml) was added with 10 wt.% palladium on activated carbon (0.294 g, 0.276 mmol). The reaction mixture was stirred under a hydrogen atmosphere (balloon pressure) for 3 h. This mixture was then filtered through celite and concentrated to give a dark oil. The crude product (phenyl 3-(6-amino-3,4-dihydroquinolin-1(2H)-yl)propyl(methyl)amine formate (830 mg, 2.445 mmol, 89% yield) ) Used directly in the subsequent reaction. ESI-MS (m/z, %) 340 (MH+, 100)

Phenylmethyl 3-(6-(thiophene-2-carboxyindoleamine)-3,4-dihydroquinolin-1(2H)-yl)propyl)aminecarboxylate:

Phenyl 3-(6-Amino-3,4-dihydroquinolin-1(2H)-yl)propyl(methyl)aminecarboxylate (830 mg, 2.445 mmol) in ethanol (35 mL) The solution was added with methylthiophene-2-carboquinone thiocarboxylate hydrogen iodide (1395 mg, 4.89 mmol) under argon. The resulting suspension was stirred at room temperature overnight. The reaction mixture was then diluted with water and sodium carbonate (sat) and extracted with dichloromethane. The combined organics were dried, filtered and concentrated, then EtOAcjjjjjjj The desired phenylmethyl (3-(6-(thiophene-2-carboxyindolinamine)-3,4-dihydroquinolin-1(2H)-yl)propyl)carbamate (630 mg) , 1.404 mmol, 57.4% yield). ¹ H NMR (DMSO- d ₆ ) δ 7.67 (d, J = 3 Hz, 1H), 7.55 (d, J = 4.8 Hz, 1H), 7.41-7.35 (m, 2H), 7.23-7.21 (m, 1H) , 7.13-7.05 (m, 3H), 6.56 (m, 2H), 6.49 (brs, 1H), 6.25 (brs, 2H), 3.50-3.45 (m, 2H), 3.38-3.32 (m, 2H), 3.23 - 3.19 (m, 2H), 3.06, 2.93 (2s, 3H), 2.69-2.64 (m, 2H), 1.89-1.81 (m, 4H).

N- (1-(3-(methylamino)propyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboxyindoleimine:

Phenylmethyl (3-(6-(thiophene-2-carboxyindoleamine)-3,4-dihydroquinolin-1(2H)-yl)propyl))carboxylic acid A solution of the ester (630 mg, 1.404 mmol) in EtOAc (EtOAc) (EtOAc) The resulting mixture was stirred at 80 ° C overnight. The reaction mixture was then cooled to room temperature, diluted with water and extracted with dichloromethane (3x). The combined organics were dried, filtered and concentrated then purified eluting elut elut elut -15% (2M NH3 in methanol) was chromatographed in dichloromethane. The yield was 130 mg (28.2%). ¹ H NMR (DMSO- d ₆ ) δ 7.66 (d, J = 3.3 Hz, 1H), 7.54 (d, J = 5.1 Hz, 1H), 7.06 (dd, J = 5.1, 3.6 Hz, 1H), 6.54 ( Brs, 2H), 6.47 (s, 1H), 6.21 (brs, 2H), 3.26-3.16 (m, 4H), 2.66 (t, J = 6.4 Hz, 2H), 2.53-2.48 (m, 2H), 2.28 (s, 3H), 1.85 (quint, J = 5.5 Hz, 2H), 1.64 (quint, J = 7.2 Hz, 2H)

Salt formation:

For N- (1-(3-(methylamino)propyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboxyindoleimide (120.5 mg, 0.367 mmol) in methanol (3mL of a solution, adding HCl, 1M in diethyl ether (0.734mL, 0.734mmol). the resulting solution was concentrated to give a yellow-orange solid 63 dihydrochloride salt. yield 163 mg.

Example 64

1-(2-morpholinoethyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (2):

6-Nitro-3,4-dihydroquinolin-2(1H)-one (1.00 g, 5.20 mmol), 4-(2-chloroethyl)morpholine hydrogen chloride (1.94 g, 10.40 mmol), iodine A suspension of sodium (390 mg, 2.61 mmol) and potassium carbonate (4.32 g, 31.3 mmol) in DMF (5 mL) The mixture was transferred to a sep. funnel, diluted with water (45 mL) and thenEtOAc. The combined organic portion was washed with brine, dried (Na ₂ SO _4), filtered and concentrated. The crude product was applied to flash chromatography using a 2.5% 2M NH ₃ in methanol / CH ₂ Cl ₂ on silica, to give a yellow solid, compound ^{2 (0.9211g, 58%) 1} H NMR (DMSO- d 6) δ 8.15 (brs , 1H), 8.12 (d, J = 2.7 Hz, 1H), 7.40 (d, J = 9.0 Hz, 1H), 4.06 (t, J = 14.1 Hz, 2H), 3.52 (t, J = 9.0 Hz, 4H) ), 2.99 (t, J = 14.7 Hz, 2H), 2.64 - 2.59 (m, 2H), 2.45 - 2.40 (m, 6H); MS-ESI (m/z, %): 306 (MH ⁺ , 100) ,219(16)

6-Amino-1-(2-morpholinoethyl)-3,4-dihydroquinolin-2(1H)-one (3):

A suspension of compound 2 (0.9211 g, 3.017 mmol) and palladium-carbon (10% wt, 0.092 g) in ethanol (10 mL) was stirred and a hydrogen balloon was charged overnight. The suspension was filtered through a pad of celite and washed with methanol (100 mL). The crude product was applied to flash chromatography on silica 2.5% 2M NH ₃ in methanol / CH ₂ Cl _2, to give a pale brown solid, compound 3 (0.802g, 96%). ¹ H NMR (DMSO- d ₆ ) δ 6.82 (d, J = 8.4 Hz, 1H), 6.45 (d, J = 2.4 Hz, 1H), 6.41 (brs, 1H), 4.85 (s, 2H), 3.89 ( t, J = 14.7 Hz, 2H), 3.54 (t, J = 9.0 Hz, 4H), 2.66 (t, J = 14.4 Hz, 2H), 2.43-2.37 (m, 8H); MS-ESI (m/z) , %): 277 (11), 276 (MH ⁺ , 100), 189 (37)

1-(2-morpholinoethyl)-1,2,3,4-tetrahydroquinolin-6-amine (4):

A mixture of compound 3 (0.800 g, 2.905 mmol) in EtOAc (EtOAc) The mixture was brought to room temperature and heated to reflux for 1 hour at this point. The reaction _{H 2 O (1mL), 3N} NaOH solution (1 mL) and an additional amount of H ₂ O (1mL) quenching. The solution was filtered over celite and rinsed with diethyl ether. The concentrated crude product was applied to a silica gel chromatography 5% 2M NH ₃ methanol / CH ₂ Cl ₂ to give a dark brown viscous liquid, Compound 4 (0.27 g, 36%) ¹ H NMR (DMSO- d ₆ ) δ 6.35 (d, J = 8.4 Hz, 1H), 6.28 (dd, J = 2.7, 8.4 Hz, 1H), 6.21 (brs, 1H), 4.18 (s, 2H), 3.55 (t, J = 9.3 Hz) , 4H), 3.22 (t, J = 14.4 Hz, 2H), 3.11 (t, J = 11.1 Hz, 2H), 2.55 (m, 2H), 2.41-2.37 (m, 6H), 1.81-1.73 (m, 2H); MS-ESI (m/z, %): 262 (MH ⁺ , 96), 147 (30), 114 (100)

N-(1-(2-morpholinoethyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboximine amide (64):

A solution of compound 4 (0.23 g, 0.88 mmol) in dry ethyl acetate (20 mL) eluted with EtOAc (EtOAc) Stir for 3 hours. The mixture was diluted with a saturated aqueous solution of sodium bicarbonate (50 mL) and evaporated. The organic layer was washed with brine (20mL) and dried (Na ₂ SO _4). The concentrated crude product was applied to a silica gel flash chromatography using 5% methanol / CH ₂ Cl ₂ to a brown foam, compound 64 (0.194 g, 59%). ¹ H NMR (CDCl ₃ ) δ 7.66 (d, J = 3.9 Hz, 1H), 7.54 (d, J = 4.5 Hz, 1H), 7.06 (dd, J = 3.6, 5.1 Hz, 1H), 6.53 (s, 2H), 6.46 (s, 1H), 6.21 (brs, 2H), 3.57 (t, J = 9.3 Hz, 4H), 3.24 (t, J = 11.4 Hz, 2H), 3.65 (t, J = 12.6 Hz, 2H), 2.45-2.41 (m, 6H), 1.88-1.80 (m, 2H); MS-ESI (m/z, %): 372 (11), 371 (MH ⁺ , 100), 258 (9); ESI-HRMS calcd for C ₂₀ H ₂₇ N ₄ OS (MH ⁺ ): Calculated: 371.1914, observed: 371.1900.

Separated mirror image isomers of Examples 65 and 66 - Example 29.

3-(6-(thiophene-2-carboxyindoleamine)-3,4-dihydroquinolin-1(2H)-yl)pyrrolidine-1-carboxylic acid tert -butyl ester ( Example 29) The mirror image mixture was separated by preparative chiral HPLC column chromatography to obtain isomer 1 and isomer 2.

Column: Chiralcel OJ-H (0.46×25cm) S/N 06-6079

Solvent: 40% isopropanol (0.1% DEA) / CO ₂ 100 bar

Wavelength: 220nm

Flow rate: 3mL/min.

The first eluted isomer was at 4.44 min. ( isomer 1 ): ESI-MS (m/z, %) 427.2 (MH ⁺ , 100%); ESI-HRMS calculated for C ₂₃ H ₃₁ N ₄ O ₂ S (MH ⁺ ), calculated: 427.2162; observed: 427.2206; chiral purity: 99.42%; chemical purity: 98.2%.

The second eluting isomer was at 5.08 min. ( isomer 2 ): ESI-MS (m/z, %) 427.2 (MH ⁺ , 100%); ESI-HRMS calculated for C ₂₃ H ₃₁ N ₄ O ₂ S (MH ⁺ ), calculated: 427.2162; observed: 427.2177; chiral purity: 99.57%; chemical purity: 97.6%.

(-)- N- (1-(pyrrolidin-3-yl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboxyindoleimine decylamine dihydrogen chloride (65) :

3-(6-(thiophene-2-carboxyindoleamine)-3,4-dihydroquinolin-1(2H)-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (same differentiation) A solution of <RTI ID=0.0></RTI></RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt; After cooling, the mixture was concentrated to dryness and dried under reduced pressure overnight. The solid was chopped in 5% isopropanol / 95% hexanes (50 mL). ESI-MS (m / z, %) 327.2 (MH +, 65%), 258.1 (100%); ESI-HRMS calcd for _{C 18 H 23 N 4 S (} MH +), calcd: 327.1637; observed Value: 326.1650; chemical purity: 97.7%; optical rotation: ²⁵ [α] ₅₈₉ = -0.19 °, c = 1.05 in MeOH.

(+)- N- (1-(pyrrolidin-3-yl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboxyindoleimine decylamine dihydrogen chloride (66)

The third butyl 3-(6-(thiophene-2-carboxyindoleamine)-3,4-dihydroquinolin-1(2H)-yl)pyrrolidine-1-carboxylate (same point A solution of the isomer 2 ) (520 mg, EtOAc, EtOAc (EtOAc) After cooling, the mixture was concentrated to dryness and dried under reduced pressure overnight. The solid was chopped in 5% isopropanol / 95% hexanes (50 mL). ESI-MS (m/z, %) 327.2 (MH ⁺ , 90%), 258.1 (100%); ESI-HRMS calc. for C ₁₈ H ₂₃ N ₄ S (MH ⁺ ), calculated: 327.1637; observed Value: 326.1635; chemical purity: 97.3%; optical rotation: ²⁵ [α] ₅₈₉ = +0.19 °, c = 0.95 in methanol.

Example 67

5-nitro-porphyrin (2):

Compound 1 (5g, 28.1mmol) in THF (10mL) of the suspension to BH ₃ -THF complexes (84mL, 84mmol, 1.0M in THF) process, and the resulting reddish brown suspension was refluxed overnight. The reaction was cooled in an ice-bath and EtOAc (EtOAc) Additional methanol (200 mL) was added and the solution was refluxed for 2 h and concentrated. The residue was applied to a large gum filter using methanol as eluent to give a brown solid (2.5 g, 54% yield). ¹ H-NMR (DMSO-d ₆ ) δ 7.90 (dd, J = 8.7, 2.4 Hz, 1H), 7.83 (s, 1H), 7.26 (s, 1H), 6.44 (d, J = 8.7 Hz, 1H) , 3.66 (t, J = 9.0 Hz, 2H), 3.04 (t, J = 9.0 Hz, 2H)

5-nitro-1-(2-(pyrrolidin-1-yl)ethyl)porphyrin (3):

A solution of compound 2 (500 mg, 3.05 mmol) in EtOAc (EtOAc) The mixture was stirred for 10 minutes then 2-chloroethyl-pyrrolidine hydrogen chloride (566 mg, 3.33 mmol) was added and the mixture was transferred to a bright red suspension. The reaction was heated to 90 ° C for 1 hour. After 1 hour, the reaction was cooled to room temperature. It was then diluted with water (20 mL), transferred to a sep. funnel and ethyl acetate (2×15 mL). The combined organic layers were washed with brine (3 × 5mL), dried (Na ₂ SO _4), filtered and concentrated. The residue was subjected to flash chromatography on silica, using: 2.5% 2M NH ₃ in MeOH: 97.5% CH ₂ Cl ₂ to give a brown solid (400mg, 50%). ¹ H-NMR (DMSO-d ₆ ) δ 7.96 (dd, J = 2.4, 9.0 Hz, 1H), 7.80 (d, J = 2.1 Hz, 1H), 6.47 (d, J = 9.0 Hz, 1H), 3.73 (t, J = 9.0 Hz, 2H), 3.41 (t, J = 6.9 Hz, 2H), 3.04 (t, J = 8.1 Hz, 2H), 2.62 (t, J = 6.9 Hz, 2H), 2.58-2.48 (m, 4H), 1.70-1.64 (m, 4H)

N- (1-(2-(pyrrolidin-1-yl)ethyl)porphyrin-5-yl)thiophene-2-carboxyindoleimine amide (6):

Compound 3 (0.40 g, 1.531 mmol) and a solution of Pd-C (0.162 g, 0.153 mmol, 10% wt) in dry ethanol (5 mL) The reaction was stirred overnight at room temperature under a hydrogen atmosphere (balloon pressure). The reaction mixture was then filtered through a pad of Celite and washed with Et. The filtrate (Compound 4 ) was imidate 5 (0.873 g, 3.06 mmol) and stirred at room temperature overnight. The reaction was diluted with saturated NaHCO ₃ solution (50mL) and the product was extracted into _{CH 2 Cl 2 (3 × 25mL} ). The combined organic layers were dried (Na ₂ SO ₄₎ and concentrated. The residue was applied to a flash chromatography on silica gel: 2% methanol: 98% CH ₂ Cl ₂ and then 5% 2M NH ₃ in methanol: 95% CH ₂ Cl ₂ to give a green/yellow solid (230 mg, 44 %). ¹ H-NMR (DMSO-d ₆ ) δ 7.68 (dd, J = 0.9, 3.6 Hz, 1H), 7.55 (dd, J = 0.9, 5.1 Hz, 1H), 7.07 (dd, J = 3.6, 4.8 Hz, 1H), 6.62 (s, 1H), 6.50-6.45 (m, 2H), 6.23 (s, 2H), 3.33 - 3.27 (m, 2H), 3.11 (t, J = 6.9 Hz, 2H), 2.84 (t , J=8.1 Hz, 2H), 2.62 (t, J = 7.5, 2H), 2.55-2.45 (m, 4H), 1.70-1.65 (m, 4H); ESI-MS (m/z, %): 341 (MH ⁺ , 100), 244 (45), 127 (57), 98 (38); ESI-HRMS calc. for C ₁₉ H ₂₅ N ₄ S (MH ⁺ ): Calculated: 341.1794, observed: 341.1788 HPLC purity: 95.3%.

Example 68

5-nitro-porphyrin (1):

He Sees 67 of Example complete experimental details and spectral data.

N,N -Dimethyl-2-(5-nitroindol-1-yl)ethylamine (2):

A solution of compound 1 (500 mg, 3.05 mmol) in EtOAc (EtOAc) Treatment with 2-chloro- N,N -dimethylethylamine hydrogen chloride (877 mg, 6.09 mmol) gave a dark red mixture. The reaction was heated to 90 ° C and stirred for 1.5 hours. After the reaction was cooled to room temperature, water (EtOAc) was evaporated. The organic layers were combined, washed with water (2 × 15mL), brine (10 mL) washed, dried (Na ₂ SO _4), filtered, and concentrated. The residue was subjected to flash chromatography on silica: CH ₂ Cl ₂ and the n 2.5% 2M NH ₃ in MeOH: 97.5% CH ₂ Cl ₂ to give a brown / red solid (400mg, 56% yield). ¹ H-NMR (DMSO-d ₆ ) δ 7.96 (dd, J = 2.1, 8.7 Hz, 1H), 7.79 (d, J = 2.1 Hz, 1H), 6.49 (d, J = 9.0 Hz, 1H), 3.72 (t, J = 8.7 Hz, 2H), 3.39 (t, J = 6.6 Hz, 2H), 3.04 (t, J = 8.7 Hz, 2H), 2.44 (t, J = 6.3, 2H), 2.18 (s, 6H)

N- (1-(2-(Dimethylamino)ethyl)porphyrin-5-yl)thiophene-2-carboxyindoleimine amide (68):

A solution of compound 2 (183 mg, 0.778 mmol) and Pd-C (82 mg, 0.078 mmol, 10% wt) in dry ethanol (5 mL) was taken up in hydrogen. The reaction was stirred overnight at room temperature under a hydrogen atmosphere (balloon pressure). The reaction mixture was then filtered through a pad of Celite and washed with Et. The filtrate (Compound 3 ) was treated with imidate 4 (444 mg, 1.459 mmol) and stirred at room temperature overnight. The reaction (50mL) and the product was diluted with saturated NaHCO ₃ solution and extracted into _{CH 2 Cl 2 (3 × 25mL} ). The combined organic layers were dried (Na ₂ SO ₄₎ and concentrated. The residue was subjected to flash chromatography on silica gel: 2% methanol: 98% CH ₂ Cl ₂ , then 2.5% 2M NH ₃ in methanol: 97.5% CH ₂ Cl ₂ , then 5% 2M NH ₃ in methanol: 95 % CH ₂ Cl ₂ to give a green/yellow solid (90 mg, yield). ¹ H-NMR (DMSO-d ₆ ) δ 7.68 (d, J = 2.7 Hz, 1H), 7.56 (dd, J = 5.1, 1.2 Hz, 1H), 7.07 (dd, J = 3.6, 5.1 Hz, 1H) , 6.62 (s, 1H), 6.55-6.46 (m, 2H), 6.28 (s, 2H), 3.32-3.27 (m, 2H), 3.09 (t, J = 6.6 Hz, 2H), 2.84 (t, J = 8.1 Hz, 2H), 2.45 (t, J = 6.9 Hz, 2H), 2.20 (s, 6H). ESI-MS (m/z, %): 315 (MH ⁺ , 100), 244 (29), 127 (38); ESI-HRMS calculated for C ₁₇ H ₂₃ N ₄ S (MH ⁺ ): 315.1637, observed: 315.1645: HPLC purity: 95.3%.

Example 69

1-(3-Chloropropyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one:

To a stirred solution of 6-nitro-3,4-dihydroquinolin-2(1H)-one (2 g, 10.41 mmol), sodium hydride, 60% (0.624 g, 15.61 mmol). The mixture was stirred at 0 ° C until bubbling ceased for about 30 minutes. To the mixture was added 1-chloro-3-iodopropane (3.29 ml, 31.2 mmol). The mixture was slowly warmed to room temperature and stirred overnight. The reaction mixture was diluted with water and extracted with EtOAc (EtOAc). The combined organic phases were washed with a 1:1 mixture of water and brine (3×) then brine (1×). The organic phase was dried, filtered and concentrated on EtOAc (EtOAc) elute Quinoline-2(1H)-one (2.05 g, 7.63 mmol, 73.3% yield) yellow solid. ¹ H NMR (DMSO- d ₆ ) δ 8.15 (m, 1H), 8.13 (dd, J=9, 2.7 Hz, 1H), 7.36 (d, J = 9 Hz, 1H), 4.07 (t, J = 7.4 Hz) , 2H), 3.71 (t, J = 6.5 Hz, 2H), 3.02 (t, J = 7.4 Hz, 2H), 2.63 (t, J = 7.4 Hz, 2H), 1.99 (quint, J = 7.2 Hz, 2H) )

1-(3-((2-Hydroxyethyl)(methyl)amino)propyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one:

1-(3-Chloropropyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (500 mg, 1.861 mmol) and potassium carbonate (1286 mg, 9.30 mmol) in stirring A mixture of acetonitrile (5 ml) was added 2-(methylamino)ethanol (0.447 ml, 5.58 mmol). The resulting mixture was stirred at room temperature overnight under argon. The reaction mixture was then diluted with water and extracted with dichloromethane (3×). The combined organics were dried, filtered and concentrated then purified eluting eluting A large amount of the starting material was recovered, and the reaction conditions were further applied, using potassium iodide, and heating at 80 ° C overnight, followed by agitation and repurification. ¹ H NMR (DMSO- d ₆ ) δ 8.15-8.10 (m, 2H), 7.41 (d, J = 8.7 Hz, 1H), 4.37 (t, J = 5.3 Hz, 1H), 3.95 (t, J = 7.4 Hz, 2H), 3.49-3.43 (m, 2H), 3.00 (t, J = 7.4 Hz, 2H), 2.62 (t, J = 7.4 Hz, 2H), 2.39-2.35 (m, 4H), 2.15 (s) , 3H), 1.66 (quint, J = 7.4 Hz, 2H)

2-(Methyl(3-(6-nitro-3,4-dihydroquinolin-1(2H)-yl)propyl)amino)ethanol:

1-(3-((2-Hydroxyethyl)(methyl)amino)propyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (200 mg, 0.651 mmol) In a borane-tetrahydrofuran complex, 1 M sol'n was stirred in THF (6.507 mL, 6.51 mmol) until material dissolved. The resulting solution was heated at 60 ° C overnight. The reaction mixture was cooled in an ice bath and quenched with methanol (slowly). The solution was concentrated, redissolved in MeOH (5 mL) and 1M EtOAc The mixture was basified with 1 M NaOH and extracted with dichloromethane (3×). The combined organics were dried, filtered and evaporated eluting elut eluting ¹ H NMR (DMSO- d ₆ ) δ 7.88 (dd, J = 9.3, 2.7 Hz, 1H), 7.77 (d, J = 2.7 Hz, 1H), 6.72 (d, J = 9.3 Hz, 1H), 4.40 ( t, J = 5.4 Hz, 1H), 3.51-3.32 (m, 6H), 2.74 (t, J = 6 Hz, 2H), 2.41-2.33 (m, 4H), 1.89-1.81 (m, 2H), 1.72 1.64 (m, 2H)

2-((3-(6-Amino-3,4-dihydroquinolin-1(2H)-yl)propyl)(methyl)amino)ethanol:

2-(Methyl(3-(6-nitro-3,4-dihydroquinolin-1(2H)-yl)propyl)amino)ethanol (76 mg, 0.259 mmol) in ethanol with stirring ( A solution of 2 mL) and tetrahydrofuran (2.0 mL) was added palladium, 10 wt% over activated carbon (27.6 mg, 0.026 mmol). The reaction mixture was stirred under a hydrogen atmosphere (balloon pressure) for 2 h. The reaction mixture was filtered through a pad of celite (methanol) and concentrated to give a dark oil. The crude product was used directly in the subsequent reaction.

N- (1-(3-((2-hydroxyethyl))(methyl)amino)propyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboxyindole Iminoguanamine (69):

2-((3-(6-Amino-3,4-dihydroquinolin-1(2H)-yl)propyl)(methyl)amino)ethanol (67 mg, 0.254 mmol) in stirring A solution of ethanol (4 ml) was added with methylthiophene-2-carboquinone thiocarboxylate hydrogen iodide (145 mg, 0.509 mmol) over argon. The resulting suspension was stirred at room temperature overnight. The reaction mixture was then diluted with water and aqueous sodium carbonate (sat) and then extracted with dichloromethane (3x). The combined organics were dried, filtered and concentrated, then purified eluted eluted eluted eluted elut . ¹ H NMR (DMSO- d ₆ ) δ 7.67 (d, J = 3.3 Hz, 1H), 7.55 (d, J = 5.1 Hz, 7.07 (t, J = 4.4 Hz, 1H), 6.55 (m, 2H), 6.48(s,1H), 6.23(brs,2H), 4.35(t,J=5.4Hz,1H),3.51-3.44(m,2H),3.24-3.17(m,4H),2.66(t,J= 6.45, 2H), 2.41-2.33 (m, 4H), 2.17 (s, 3H), 1.89-1.81 (m, 2H), 1.63 (quint, J = 7 Hz, 2H). ESI-MS (m/z, % 373 (MH+, 100), 258 (31), 187 (49), 127 (42). ESI-HRMS calc. for C20H29N40S (MH+), calculated: 373.2056, observed: 373. 2052

Examples 70 and 71

1-(1,4-Dioxaspiro[4.5]dec-8-yl)porphyrin (3):

After Compound 1 (2.0g, 16.78mmol) and compound 2 (3.15g, 20.139mmol) in anhydrous methanol (20mL) of solution, acetic acid (2.4mL, 42.00mmol), so as to NaCNBH ₃ (1.26g, 20.14mmol ) was processed at 0 °C. The resulting mixture was brought to room temperature and stirred for 3 h. The reaction was basified with 1N NaOH solution (50 mL) and EtOAc (EtOAc) The combined ethyl acetate layer was washed with brine (25mL) and dried (Na ₂ SO _4). The solvent was evaporated and the crude product was purified by column chromatography (ethyl acetate: hexane, 1: 4) to give compound 3 (3.52g, 81%) solid. ¹ H NMR (CDCl ₃ ) δ 7.06-7.02 (m, 2H), 6.59 (t, J = 14.7 Hz, 1H), 6.42 (d, J = 8.1 Hz, 1H), 3.46 (s, 4H), 3.46- 3.35 (m, 3H), 2.93 (t, J = 16.5 Hz, 2H), 1.87-1.60 (m, 8H). MS-ESI (m/z, %): 262 (8), 260 (MH ⁺ , 100), 120 (28)

5-bromo-1-(1,4-dioxaspiro[4.5]dec-8-yl)porphyrin (4):

A solution of compound 3 (3.45 g, 13.30 mmol) in dry EtOAc (EtOAc) The reaction was stirred at the same temperature for 3.5 h. The reaction was diluted with water (200 mL) and EtOAc (EtOAc) The combined ethyl acetate layers with water (2 × 50mL), brine (25mL) and dried (Na ₂ SO _4). The solvent was evaporated, and the crude product was purified by column chromatography on silica (ethyl acetate: hexane, 1: 4) to give compound 4 (4.05g, 90%) pulp. ¹ H NMR (CDCl ₃ ) δ 7.12-7.10 (m, 2H), 6.25 (d, J = 9.0 Hz, 1H), 3.95 (s, 4H), 3.38 (t, J = 16.8 Hz, 3H), 2.91 ( t, J = 16.8 Hz, 2H), 1.86-1.57 (m, 8H). MS-ESI (m/z, %): 340 (98), 338 (M ⁺ , 100), 198 (18)

4-(5-bromoporphyrin-1-yl)cyclohexanone (5):

A solution of compound 4 (4.0 g, 11.83 mmol) inEtOAc (EtOAc) The acetone was evaporated, the crude was basified to 2N NaOH solution, the product was extracted into _{CH 2 Cl 2 (3 × 25mL} ). The combined of CH ₂ Cl ₂ layer was washed with brine (20mL) and dried (Na ₂ SO _4). The solvent was evaporated and the crude product was purified by column chromatography on silica (ethyl acetate: hexane, 1: 4) to give Compound 5 (2.9g, 83%) solid. ¹ H NMR (CDCl ₃ ) δ 7.15 (d, J = 6.6 Hz, 2H), 6.32 (d, J = 8.7 Hz, 1H), 3.81 (tt, J = 7.2, 23.4 Hz, 1H), 3.37 (t, J = 16.8 Hz, 2H), 2.95 (t, J = 16.5 Hz, 2H), 2.51-2.41 (m, 4H), 2.18-2.11 (m, 2H), 1.92-1.78 (m, 2H). MS-ESI (m/z, %): 296 (96), 294 (M ⁺ , 100), 200 (30)

4-(5-Bromoporphyrin-1-yl) -N -methylcyclohexylamine (6a and b):

A solution of compound 5 (0.5 g, 1.70 mmol), methylamine hydrogen chloride (0.11 g, 1.70 mmol) in anhydrous 1 ,2-dichloroethane (10 mL) Sodium triethoxy borohydride (0.54 g, 2.55 mmol) was taken at 0 °C. The resulting mixture was brought to room temperature and stirred for 3 h. The reaction was basified with 1N NaOH solution (50 mL) and EtOAc (EtOAc) The combined ethyl acetate layer was washed with brine (25mL) and dried (Na ₂ SO _4). The solvent was evaporated and the crude product was purified by column chromatography on silica to (2M NH ₃ in _{MeOH: CH 2 Cl 2, 2} : 98) to obtain a compound 6a (0.35g, 94%) and 6 b (0.43g, 92 %) Partially separated non-image isomer mixture. Compound 6a (non-polar isomer, higher rf) : ¹ H NMR (DMSO-d6) δ 7.09-7.04 (m, 2H), 6.35 (d, J = 8.1 Hz, 1H), 3.36-3.26 ( m, 2H), 2.85 (t, J = 16.8 Hz, 2H), 2.59 (t, 1H), 2.23 (s, 3H), 1.80-1.63 (m, 5H), 1.51-1.33 (m, 5H). MS-ESI (m/z, %): 311 (MH ⁺ , 94), 309 (M ⁺ , 100), 112 (8). Compound 6b (polar isomer, lower rf) : ¹ H NMR (DMSO-d6) δ 7.09-7.05 (m, 2H), 6.36 (d, J = 8.1 Hz, 1H), 3.34 - 3.29 (m) , 3H), 2.85 (t, J = 16.8 Hz, 2H), 2.30-2.16 (m, 5H), 1.93 (d, J = 12.0 Hz, 2H), 1.67 (d, J = 11.1 Hz, 2H), 1.45 -1.32 (m, 2H), 1.32-1.02 (m, 2H). MS-ESI (m/z, %): 311 (13), 309 (M ⁺ , 8), 280 (93), 278 (100)

T-butyl 4-(5-bromoindoline-1-yl)cyclohexyl (methyl)aminecarboxylate (7a, non-polar isomer):

Compound 6a (0.28g, 0.905mmol) in anhydrous 1,4-dioxane (5mL) of the solution, triethyl amine (0.25mL, 1.811mmol) process, then two-butyl dicarbonate third ( Treated with 0.20 g, 0.951 mmol) and stirred at rt overnight. The reaction was diluted in 1N NaOH and the product solution (20mL) and extracted into _{CH 2 Cl 2 (2 × 20mL} ). The combined of CH ₂ Cl ₂ layer was washed with brine (20mL) and dried (Na ₂ SO _4). The solvent was evaporated and the crude product was purified by column chromatography on silica (2M NH ₃ in _{methanol: CH 2 Cl 2, 2.5:} 97.5) to obtain compound 7a (0.35g, 94%) pulp. ¹ H NMR (CDCl ₃ ) δ 7.14-7.10 (m, 2H), 6.32 (d, J = 8.1 Hz, 1H), 4.02-3.98 (m, 1H), 3.70 (s, 2H), 3.56 (t, J) =16.2 Hz, 2H), 3.31 (t, J = 6.6 Hz, 1H) 2.94 (t, J = 16.2 Hz, 2H), 2.79-2.74 (m, 3H), 2.13 (d, J = 13.2 Hz, 2H) , 1.81-1.67 (m, 4H), 1.46 (s, 9H). MS-ESI (m/z, %): 411 (61), 409 (M ⁺ , 58), 331 (100), 275 (37)

T-butyl 4-(5-bromoindoline-1-yl)cyclohexyl (methyl)aminecarboxylate (7b, Polar isomers):

Compound 6b (0.355g, 1.148mmol) was in dry 1,4-dioxane (5mL), the triethyl amine (0.32 mL, 2.296 mmol), and then to two third-butyl dicarbonate (0.26 Treated with g, 1.205 mmol) and stirred at room temperature overnight. The reaction was diluted with 1N NaOH solution (20mL) and extracted into _{CH 2 Cl 2 (2 × 20mL} ) product. The combined of CH ₂ Cl ₂ layer was washed with brine (20mL) and dried (Na ₂ SO _4). The solvent was evaporated and the crude product was purified by column chromatography on silica (2M NH ₃ in _{MeOH: CH 2 Cl 2, 2.5} : 97.5) to give compound 7b (0.43g, 92%) pulp. ¹ H NMR (CDCl ₃ ) δ 7.12 (brs, 2H), 6.27 (d, J = 7.8 Hz, 1H), 3.96-3.92 (m, 1H), 3.70 (s, 2H), 3.37 (t, J = 16.8) Hz, 2H), 3.32-3.23 (m, 1H), 2.93 (t, J = 16.8 Hz, 2H), 2.80-2.74 (m, 4H), 1.91-1.73 (m, 5H), 1.52 (s, 9H) . MS-ESI (m/z, %): 411 (MH ⁺ , 14), 409 (M ⁺ , 14), 331 (100), 275 (37), 156 (85)

T-butyl 4-(5-aminoporphyrin-1-yl)cyclohexyl (methyl)aminecarboxylate (8a, non-polar isomer):

The _{Pd 2 (dba) 3 (0.040g} , 0.04397mmol) in dry THF (5mL) of the solution to PtBu ₃ (10% in hexanes, 0.534mL, 0.1759mmol) process. This mixture was treated with compound 7a (0.36 g, 0.8794 mmol) in dry THF (15 mL) This solution was stirred at 100 ° C for 3 hours. This solution was quenched with 1 M TBAF in THF (2 mL) and stirred for 20 min. The reaction was diluted with 3N NaOH solution (50 mL) andEtOAcEtOAc The organic layer was dried (Na ₂ SO ₄₎ and concentrated. The crude product was applied to silica gel flash chromatography using a _{2.5% 2M NH 3 MeOH / CH} 2 Cl 2, to give a dark brown foam, compound 8a (0.283g, 93%)

T-butyl 4-(5-aminoporphyrin-1-yl)cyclohexyl (methyl)aminecarboxylate (8b, polar isomer):

The _{Pd 2 (dba) 3 (0.047g} , 0.0513mmol) in anhydrous THF (5mL) of the solution to PtBu ₃ (10% in hexanes, 0.622mL, 0.2052mmol) process. This mixture was treated with compound 7b (0.42 g, 1.026 mmol) in dry THF (15 mL) This solution was stirred at 100 ° C for 3 hours. The solution was quenched with 1 M TBAF in THF (2 mL) and stirred for 20 min. The reaction was diluted with 3N NaOH solution (50 mL) andEtOAcEtOAc The organic layer was dried (Na ₂ SO ₄₎ and concentrated. The crude product was applied to silica gel flash chromatography using a _{2.5% 2M NH 3 MeOH / CH} 2 Cl 2, to give a dark brown foam, compound 8b (0.3495g, 98%)

Tertiary butyl methyl (4- (5- (thiophene-2-carboxamide (PEI) Amides) indol-1-yl) cyclohexyl) carbamate (9a, a non-polar isomers thereof) :

A solution of compound 8a (0.283 g, 0.8192 mmol) in dry ethyl acetate (20 mL) eluted with methyl thiophene-2-carbophthalide thiocarboxylate hydrogen hydride (1.6345 g, 5.7344 mmol) at room temperature Stir for 3 hours. The mixture was diluted with a saturated aqueous solution of sodium bicarbonate (50 mL) and evaporated. The organic layer was washed with brine (20mL) and dried (Na ₂ SO _4). The concentrated crude product was applied to the flash chromatographed on silica using 2.5% methanol / CH ₂ Cl _2, to give a brown foam, Compound 9a (0.2507g, 67%). ¹ H NMR (DMSO- d ₆ ) δ 7.68 (d, J = 3.6 Hz, 1H), 7.56 (d, J = 5.1 Hz, 1H), 7.07 (dd, J = 3.9, 8.7 Hz, 1H), 6.63 ( Brs, 1H), 6.51 (d, J = 7.5 Hz, 1H), 6.42 (d, J = 8.4 Hz, 1H), 6.28 (brs, 2H), 3.88-3.81 (m, 1H), 3.45 (t, J =15.9 Hz, 2H), 3.26-3.24 (m, 1H), 2.84 (t, J = 15.6 Hz, 2H), 2.72 (s, 3H), 2.10-2.06 (m, 2H), 1.81-1.74 (m, 2H), 1.66-1.57 (m, 2H), 1.51-1.46 (m, 2H), 1.40 (s, 9H). MS-ESI (m/z,%): 455 (MH ⁺ , 100)

Third butylmethyl (4-(5-(thiophene-2-carboxyindolinamine) porphyrin-1-yl)cyclohexyl)carbamate (9b, polar isomer):

A solution of compound 8b (0.3316 g, 0.9598 mmol) in dry ethyl acetate (20 mL) eluted with methyl thiophene-2-carbophthalide thiocarboxylate hydrogen peroxide (1.642 g, 5.760 mmol) at room temperature Stir for 3 hours. The mixture was diluted with a saturated aqueous solution of sodium bicarbonate (50 mL) and evaporated. The organic layer was washed with brine (20mL) and dried (Na ₂ SO _4). The concentrated crude product was applied to the flash chromatographed on silica using _{2.5% MeOH / CH 2 Cl 2} , to give a brown foam, compound 9b (0.3768g, 86%). ¹ H NMR (DMSO- d ₆ ) δ 7.68 (d, J = 3.0 Hz, 1H), 7.56 (d, J = 5.1 Hz, 1H), 7.07 (t, J = 9.0 Hz, 1H), 6.62 (brs, 1H), 6.54 (d, J = 8.4 Hz, 1H), 6.41 (d, J = 8.4 Hz, 1H), 6.30 (brs, 2H), 3.81-3.77 (m, 1H), 3.28-3.25 (m, 2H) ), 2.83 (t, J = 16.2 Hz, 2H), 2.68 (s, 3H), 1.78 (d, J = 10.8 Hz, 2H), 1.64-1.62 (m, 4H), 1.50-1.46 (m, 2H) , 1.40 (s, 9H). MS-ESI (m/z,%): 455 (MH ⁺ , 100)

N- (1-(4-(methylamino)cyclohexyl)porphyrin-5-yl)thiophene-2-carboxyindoleimine amide (70, non-polar isomer):

A solution of compound 9a (0.2314 g, 0.5090 mmol) elut elut elut elut elut elut elut elut The reaction was taken to room temperature, concentrated and concentrated under reduced pressure. The product, compound 70, dihydrochloride salt was taken to a free base, and flash chromatography was applied to silica gel using 10% methanol / CH ₂ Cl ₂ (0.1451 g, 81%). ¹ H NMR (DMSO- d ₆ ) δ 7.67 (d, J = 3.0 Hz, 1H), 7.54 (d, J = 5.1 Hz, 1H), 7.06 (t, J = 8.7 Hz, 1H), 6.60 (brs, 1H), 6.51 (d, J = 8.1 Hz, 1H), 6.38 (d, J = 8.1, 1H), 6.21 (brs, 2H), 3.32-3.25 (m, 4H), 2.82 (t, J = 16.8 Hz) , 2H), 2.62 (brs, 1H), 2.25 (s, 3H), 1.81-1.66 (m, 4H), 1.53-1.39 (m, 4H). MS-ESI (m/z, %): 355 (MH ⁺ , 82), 324 (100), 244 (17), 133 (21); ESI-HRMS calculated for C ₂₀ H ₂₇ N ₄ S (MH ⁺ ): Calculated value: 355.1949, observed: 355.1950.

N- (1-(4-(methylamino)cyclohexyl)porphyrin-5-yl)thiophene-2-carboxyindoleimine amide (71, polar isomer):

A solution of compound 9b (0.3768 g, 0.8288 mmol) in EtOAc (EtOAc) The reaction was taken to room temperature, concentrated and concentrated under reduced pressure. The product, compound 71, prepared dihydrochloride salt into the free base, and applied to flash chromatography using _{10% MeOH / CH 2 Cl 2} (0.1933g, 66%) on silica. ¹ H NMR (DMSO- d ₆ ) δ 7.67 (d, J = 3.3 Hz, 1H), 7.54 (d, J = 5.1 Hz, 1H), 7.06 (t, J = 8.7 Hz, 1H), 6.60 (brs, 1H), 6.52 (d, J = 8.1, 1H), 6.21 (brs, 2H), 3.31-3.24 (m, 4H), 3.16 (s, 1H), 2.82 (t, J = 16.5 Hz, 2H), 2.31 - 2.19 (m, 4H), 1.95 (d, J = 11.4 Hz, 2H), 1.73 (d, J = 11.4 Hz, 2H), 1.47-1.35 (m, 2H), 1.16-1.04 (m, 2H). MS-ESI (m/z, %): 355 (MH ⁺ , 100), 324 (81), 141 (26), 133 (35); ESI-HRMS calculated for C ₂₀ H ₂₇ N ₄ S (MH ⁺ ): Calculated value: 355.1935, observed: 355.1950.

Example 72

1-(3-morpholinylpropyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one:

1-(3-Chloropropyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (500 mg, 1.861 mmol) and potassium carbonate (1286 mg, 9.30 mmol) in stirring A suspension of acetonitrile (10 ml) was added to the morpholine (0.814 ml, 9.30 mmol) via a syringe. The resulting suspension was stirred at 75 ° C in a sealed tube overnight. The reaction mixture was then cooled to room temperature, diluted with water and extracted with dichloromethane (3x). The combined organics were dried, filtered and evaporated eluted elut elut elut elut elut elut elut elut elut -6-Nitro-3,4-dihydroquinolin-2(1H)-one (560 mg, 1.754 mmol, 94% yield). ¹ H NMR (DMSO- d ₆ ) δ 8.14-8.10 (m, 2H), 7.40 (d, J = 9 Hz, 1H), 3.95 (t, J = 7.4 Hz, 2H), 3.58-3.54 (m, 4H) , 3.03-2.97 (m, 2H), 2.64-2.59 (m, 2H), 2.33-2.28 (m, 6H), 1.74-1.64 (m, 2H)

4-(3-(6-Nitro-3,4-dihydroquinolin-1(2H)-yl)propyl)morpholine:

1-(3-Morpholinylpropyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (550 mg, 1.722 mmol) in borane tetrahydrofuran complex, 1M in THF (17.200 mL, 17.20 mmol) was stirred at reflux temperature overnight. The reaction mixture was then cooled to 0.degree. C. and quenched with methanol (10 mL). The solution was concentrated, and the residue was redissolved in EtOAc (EtOAc)EtOAc. The mixture was neutralized and basified with 3N NaOH and extracted with dichloromethane (3×). The combined organics were dried, filtered and concentrated, then purified eluting eluting eluting with Base-3,4-dihydroquinolin-1(2H)-yl)propyl)morpholine (260 mg, 0.851 mmol, 49.4% yield). ¹ H NMR (DMSO- d ₆ ) δ 7.87 (dd, J = 9.3, 2.7 Hz, 1H), 7.77 (d, J = 2.7 Hz, 1H), 6.72 (d, J = 9.3 Hz, 1H), 3.60- 3.56 (m, 4H), 3.45-3.39 (m, 4H), 2.74 (t, J = 6 Hz, 2H), 2.35-2.26 (m, 6H), 1.88-1.80 (m, 2H), 1.76-1.66 (m , 2H)

1-(3-morpholinylpropyl)-1,2,3,4-tetrahydroquinolin-6-amine:

4-(3-(6-Nitro-3,4-dihydroquinolin-1(2H)-yl)propyl)morpholine (250 mg, 0.819 mmol) in ethanol (4 ml) and tetrahydrofuran A solution of 4.00 ml) was added palladium on activated carbon, 10 wt.% (87 mg, 0.082 mmol). The reaction was stirred under a hydrogen atmosphere (balloon pressure) for 2 h. When the TLC analysis indicated that the starting material had been consumed, the mixture was filtered through a pad of Celite and then washed with methanol. The filtrate was concentrated to give the desired 1-(3-morpholinylpropyl)-1,2,3,4-tetrahydroquinolin-6-amine (190 mg, 0.690 mmol, 84% yield) of dark oil.

N- (1-(3-morpholinopropyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboxyindoleimine:

A solution of 1-(3-morpholinylpropyl)-1,2,3,4-tetrahydroquinolin-6-amine (190 mg, 0.690 mmol) in ethanol (10 mL) Methylthiophene-2-carbonium imine thiocarboxylate hydrogen iodide (393 mg, 1.380 mmol). The resulting suspension was stirred overnight at room temperature. The mixture was then diluted with water and sodium carbonate and extracted with dichloromethane (3×). The combined organic phase was dried, filtered and concentrated, then chromatographed in ethyl acetate, then 5-10% (2M NH3 in MeOH) in dichloromethane chromatography to give the expectations N - (1- (3- do Phenylpropyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboxyindoleimine decylamine 72 (132 mg, 0.343 mmol, 49.8% yield). ¹ H NMR (DMSO- d ₆ ) δ 7.67 (d, J = 3 Hz, 1H), 7.56 (d, J = 4.8 Hz, 1H), 7.09-7.06 (m, 1H), 6.56 (brs, 2H), 6.49 (s, 1H), 6.33 (brs, 2H), 3.60-3.56 (m, 4H), 3.26-3.17 (m, 4H), 2.66 (t, J = 6.3 Hz, 2H), 2.34 - 2.28 (m, 6H) ), 1.89-1.81 (m, 2H), 1.69-1.63 (m, 2H). ESI-MS (m/z, %) 384 (100, MH+), 270 (52). HPLC purity: 99%.

Example 73 (isomer 1)

1-(1,4-Dioxaspiro[4.5]dec-8-yl)-1,2,3,4-tetrahydroquinoline (3):

A solution of compound 1 (0.2 g, 1.502 mmol) and compound 2 (0.28 g, 1.802 mmol) in anhydrous 1,2-dichloroethane (5 mL), acetic acid (0.085 mL, 1.502 mmol) Sodium oxahydride borohydride (0.38 g, 1.802 mmol) was treated at 0 °C. The resulting mixture was brought to room temperature and stirred for 3 h. The reaction was basified with 1N NaOH solution (20 mL) and EtOAc (EtOAc) The combined ethyl acetate layer was washed with brine (15mL) and dried (Na ₂ SO _4). The solvent was evaporated and the crude product was purified by column chromatography (ethyl acetate: hexane, 1: 4) to give compound 3 (0.22g, 53.6%) pulp. ¹ H NMR (CDCl ₃ ) δ 7.06 (t, 1H, J = 7.8 Hz), 6.95 (d, 1H, J = 7.2 Hz), 6.67-6.55 (m, 2H), 3.96 (s, 4H), 3. 3.63 (m, 1H), 3.21 (t, 2H, J = 5.4 Hz), 2.72 (t, 2H, J = 6.3 Hz), 1.92-1.63 (m, 10H); ESI-MS (m/z, %) 274 (MH ⁺ , 100).

6-Bromo-1-(1,4-dioxaspiro[4.5]dec-8-yl)-1,2,3,4-tetrahydroquinoline (4):

A solution of compound 3 (0.19 g, 0.695 mmol) elute elut elut elut elut elut elut The reaction was stirred at the same temperature for 3.5 h. The reaction was diluted with water (50 mL) and EtOAc (EtOAc) The combined ethyl acetate layers were washed with water (2 × 20mL), brine (15mL) and dried (Na ₂ SO _4). The solvent was evaporated and the crude mixture was purified by column chromatography on silica to (ethyl acetate: hexane, 1: 9) to give Compound 4 (0.225g, 92%) pulp. ¹ H NMR (CDCl ₃ ) δ 7.16-7.05 (m, 2H), 6.60-6.52 (m, 1H), 3.96 (s, 4H), 3.64-3.55 (m, 1H), 3.20 (t, 2H, J = 5.7 Hz), 2.69 (t, 2H, J = 6.0 Hz), 1.91-1.54 (m, 10H); ESI-MS (m/z, %): 352, 354 (MH ⁺ , 100)

4-(6-Bromo-3,4-dihydroquinolin-1(2H)-yl)cyclohexanone (5):

A solution of compound 4 (0.21 g, 0.596 mmol) inEtOAc (EtOAc) The acetone was evaporated, the crude product was extracted with 2N NaOH solution and the product was basified to _{CH 2 Cl 2 (2 × 15mL} ). The combined CH ₂ Cl ₂ layer was washed with brine (10 mL) and dried (Na ₂ SO _4). The solvent was evaporated to give a compound 5 (0.18 g, 98%). ¹ H NMR (CDCl ₃ ) δ 7.16 (dd, 1H, J = 2.4, 4.3 Hz), 7.08 (s, 1H), 6.60 (d, 1H, J = 9.0 Hz), 4.11-4.01 (m, 1H), 3.17 (t, 2H, J = 5.7 Hz), 2.71 (t, 2H, J = 6.3 Hz), 2.52 - 2.48 (m, 4H), 2.14-1.85 (m, 6H); ESI-MS (m/z, %): 308,310 (MH ⁺ ,100)

4-(6-Bromo-3,4-dihydroquinolin-1(2H)-yl)-N-methylcyclohexylamine (6 and 7):

A solution of compound 5 (0.16 g, 0.519 mmol) and methylamine hydrogen chloride (0.035 g, 0.519 mmol) in anhydrous <RTI ID=0.0> Sodium triethoxy borohydride (0.165 g, 0.779 mmol) was taken at 0 °C. The resulting mixture was brought to room temperature and stirred overnight. The reaction 1N NaOH solution (25mL) and basified and the product was extracted into _{CH 2 Cl 2 (2 × 20mL} ). The combined CH ₂ Cl ₂ layer was washed with brine (15mL) and dried (Na ₂ SO _4). The solvent was evaporated and the crude product was purified by column chromatography (ethyl acetate: hexane, 1: 4) to give compound 6 and 7 (0.14g, 83%) diastereomeric mixture of partially separated. Compound 6: syrup, ¹ H NMR (DMSO- d ₆ ) δ 7.04 (dd, 1H, J = 2.4, 8.8 Hz), 6.99 (d, 1H, J = 2.4 Hz), 6.58 (d, 1H, J = 9.0 Hz), 3.54-3.48 (m, 1H), 3.14 (t, 2H, J = 5.7 Hz), 2.67-2.60 (m, 3H), 2.26 (s, 3H), 1.88-1.71 (m, 7H), 1.57 - 1.47 (m, 2H), 1.38-1.32 (m, 2H); ESI-MS (m/z, %): 323, 325 (MH ⁺ , 100). Compound 7: syrup, ¹ H NMR (DMSO- d ₆ ) δ 7.05 (dd, 1H, J = 2.7, 8.8 Hz), 6.99 (d, 1H, J = 2.4 Hz), 6.57 (d, 1H, J = 9.0 Hz), 3.54-3.47 (m, 1H), 3.12 (t, 2H, J = 5.7 Hz), 2.62 (t, 2H, J = 6.3 Hz), 2.27 (s, 3H), 2.24 - 2.18 (m, 1H) ), 1.93 (d, 2H, J = 12.0 Hz), 1.79-1.45 (m, 7H), 1.23-1.06 (m, 2H); ESI-MS (m/z, %): 325, 323 (MH ⁺ , 30) ,292,294(100)

4-(6-Bromo-3,4-dihydroquinolin-1( 2H ))cyclobutyl(methyl)aminecarboxylic acid tert -butyl ester (8):

Compound 6 (0.408g, 1.262mmol) in dioxane solution (10 mL), the triethyl amine (0.532mL, 3.79mmol), and Boc ₂ O (0.303g, 1.388mmol), so as to give an orange - Yellow suspension and stirred at room temperature overnight. The reaction mixture was diluted and the product in 1N NaOH (20mL) and extracted into _{CH 2 Cl 2 (3 × 20mL} ). The combined organic layers were washed with brine (15mL), dried (Na ₂ SO _4), and concentrated. The residue was subjected to flash chromatography on silica: 2.5% 2M NH ₃ in MeOH: 97.5% CH ₂ Cl _2, to give a solid. (435 mg, 81% yield). ¹ H NMR (DMSO- d ₆ ) δ 7.07 (dd, J = 8.7, 2.4 Hz, 1H), 7.02 (d, J = 2.4 Hz, 1H), 6.54 (d, J = 9.0 Hz, 1H), 3.93 3.85 (m, 1H), 3.72- 3.66 (m, 1H), 3.32-3.24 (m, 2H), 2.80 (s, 3H), 2.65 (t, J = 6.3 Hz, 2H), 1.95-1.73 (m, 6H), 1.67-1.54 (m, 4H), 1.40 (s, 9H)

Methyl (4- (6- (thiophene-2-carboxamide (PEI) Amides -) - 3,4-dihydro-quinoline -1 (2H) - yl) cyclohexyl) amine acid tert-butyl ester (11) :

Add a compound of Pd ₂ dba ₃ (0.047 g, 0.051 mmol) and tri-tert-butylphosphine (10% wt in hexane, 0.868 ml, 0.203 mmol) in THF (3 mL) in a microwave vial 8 (0.430 g, 1.016 mmol) in THF (7 mL). This mixture was treated with lithium bis(trimethyldecyloxy) decylamine (1M in THF, EtOAc (EtOAc) The microwave vial was capped and heated to 90 °C for 3 hours. Tetrabutylammonium fluoride (1 M in THF, 4 mL) was added and the solution was stirred for half an hour. The reaction mixture was diluted with 1N NaOH (50mL), and extracted into _{CH 2 Cl 2 (3 × 25mL} ) product. The combined organic layers were dried (Na ₂ SO _4), and concentrated. The residue was subjected to flash chromatography on silica: CH ₂ Cl _2, then to 2.5% 2M NH ₃ in _{MeOH: 97.5% CH 2 Cl 2} , to give a solid (Compound 9). A suspension of compound 9 and compound 10 (0.678 g, 2.377 mmol) in ethanol (10 mL) was stirred at room temperature overnight. The reaction was diluted with saturated NaHCO ₃ solution (50mL) and the product was extracted into _{CH 2 Cl 2 (3 × 25mL} ). The combined organic layers were dried (Na ₂ SO ₄₎ and concentrated. The residue was subjected to flash chromatography on silica gel: 50% ethyl acetate: 50% hexane, then 2.5% methanol: 97.5% CH ₂ Cl ₂ to yield a solid (250 mg, 52.5% yield). ¹ H NMR (DMSO- d ₆ ) δ 7.67 (d, J = 3.9 Hz, 1H), 7.55 (d, J = 5.1 Hz, 1H), 7.07 (dd, J = 4.8, 3.9 Hz, 1H), 6.61 6.50 (m, 3H), 6.24 (s, 2H), 3.92-3.89 (m, 1H), 3.67-3.65 (m, 1H), 3.24 (t, J = 5.7 Hz, 2H), 2.80 (s3H), 2.66 (t, J = 6.3 Hz, 2H), 1.99-1.70 (m, 6H), 1.65-1.54 (m, 4H), 1.40 (s, 9H)

N- (1-(4-(methylamino)cyclohexyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboxyindoleimide (73):

A solution of compound 11 (250 mg, 0.533 mmol) elut elut elut elut elut elut And the residue was partitioned between CH ₂ Cl ₂ (25mL) in 3N NaOH (50mL), and the product was extracted into _{CH 2 Cl 2 (2 × 25mL} ). The combined organic layers were dried (Na ₂ SO ₄₎ and concentrated. The residue was subjected to flash chromatography on silica: 2% MeOH: 98% CH 2 Cl 2, then to 2.5% 2M ammonia in methanol; 97.5% CH ₂ Cl ₂ to give a yellow-brown solid. (156 mg, 79% yield) ¹ H NMR (DMSO- d ₆ ) δ 7.66 (d, J = 2.7 Hz, 1H), 7.54 (dd, J = 0.9, 5.1 Hz, 1H), 7.06 (dd, J = 3.6 , 4.8 Hz, 1H), 6.63-6.41 (m, 3H), 6.21 (s, 2H), 3.55-3.46 (m, 1H), 3.35-3.30 (m, 1H) 3.13 (t, J = 5.7 Hz, 2H ), 2.63 (t, J = 6.0 Hz, 2H), 2.26 (s, 3H), 2.10 - 1.75 (m, 6H), 1.60-1.45 (m, 2H), 1.39-1.32 (m, 2H). ESI-MS (m/z, %): 369 (MH ⁺ , 96), 338 (48), 258 (100), 185 (20), 148 (24), 140 (20); For C ₂₁ H ₂₉ N ₄ S(MH ⁺ ): 369.2107, observed: 369.2112; HPLC purity: 95.3%.

Example 74 (isomer 2)

4-(6-Bromo-3,4-dihydroquinolin-1(2 H )-yl) -N -methylcyclohexylamine (1):

Reference example 73 (Compound 7)

3-(6-Bromo-3,4-dihydroquinolin-1( 2H )-yl)cyclohexane(methyl)aminecarboxylic acid tert -butyl ester (2):

Compound 1 (0.38g, 1.175mmol) in dioxane solution (10 mL), the triethyl amine (0.495mL, 3.53mmol), and Boc ₂ O (0.282g, 1.293mmol), so as to give an orange - Yellow suspension and stirred at room temperature overnight. The reaction mixture was diluted with 1N NaOH (20mL), and extracted into _{CH 2 Cl 2 (3 × 20mL} ) product. The combined organic layers were washed with brine (15mL), dried (Na ₂ SO _4), and concentrated. The residue was subjected to flash chromatography on silica: 2.5% 2M NH ₃ in MeOH: 97.5% CH ₂ Cl _2, to give a solid. (456 mg, 92% yield). ¹ H NMR (DMSO- d ₆ ) δ 7.07 (dd, J = 2.7, 9.0 Hz, 1H), 7.00 (d, J = 2.7 Hz, 1H), 6.62 (d, J = 9.0 Hz, 1H), 3.62 3.53 (m, 2H), 3.134 (t, J = 5.7 Hz, 2H), 2.69 (s, 3H), 2.63 (t, J = 6.3 Hz, 2H), 1.80-1.53 (m, 10H), 1.40 (s) , 9H)

Methyl (4- (6- (thiophene-2-carboxamide (PEI) Amides -) - 3,4-dihydro-quinoline -1 (2H) - yl) cyclohexyl) amine acid tert-butyl ester (5) :

Into a microwave vial, a suspension of Pd ₂ dba ₃ (0.049 g, 0.053 mmol) and tri-tert-butylphosphine (10% wt in hexane, 0.91 mL, 0.203 mmol) in THF (3 mL) Compound 2 (0.430 g, 1.016 mmol) in EtOAc (EtOAc) This mixture was treated with bis(trimethyldecyloxy) guanamine (1M in THF, 2.031 mL, 2.031 mmol) to afford a dark brown suspension. The microwave vial was capped and heated to 90 °C for 3 hours. TBAF (1 M in THF, 4 mL) was added and the solution was stirred for half an hour. The reaction mixture was diluted with 1N NaOH (50mL), and the product was extracted into _{CH 2 Cl 2 (3 × 25mL} ). The combined organic layers were dried (Na ₂ SO _4), and concentrated. The residue was subjected to flash chromatography on silica gel: CH ₂ Cl ₂ and then 2.5% 2M NH ₃ in methanol: 97.5% CH ₂ Cl ₂ to give a solid (comp. 3 ). A suspension of compound 3 and compound 4 (0.606 g, 2.125 mmol) in ethanol (10 mL) was stirred at room temperature overnight. The reaction was diluted with saturated NaHCO ₃ solution (50mL) and the product was extracted into _{CH 2 Cl 2 (3 × 25mL} ). The combined organic layers were dried (Na ₂ SO ₄₎ and concentrated. The residue was subjected to flash chromatography on silica gel: 50% ethyl acetate: 50% hexane, then 2.5% methanol: 97.5% CH ₂ Cl ₂ to yield a solid (250 mg, 50.0% yield). ¹ H NMR (DMSO- d ₆ ) δ 7.67 (d, J = 4.2 Hz, 1H), 7.55 (dd, J = 0.6, 4.8 Hz, 1H), 7.07 (dd, J = 3.9, 5.1 Hz, 1H), 4.03-4.01(m,1H), 3.60-3.57(m,1H), 3.12(t,J=5.4Hz,2H), 2.70(s,3H),2.64(t,J=6.3Hz,2H),1.84 -1.60 (m, 10H), 1.40 (s, 9H).

N- (1-(4-(methylamino)cyclohexyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboxyindoleimine (74):

A solution of compound 5 (250 mg, 0.533 mmol) in EtOAc (EtOAc) The residue in 3N NaOH (50mL) and between CH ₂ Cl ₂ (25mL) layers were separated and the product was extracted into _{CH 2 Cl 2 (2 × 25mL} ). The combined organic layers were dried (Na ₂ SO _4), and concentrated. The residue was subjected to flash chromatography on silica gel: 2% methanol: 98% CH ₂ Cl ₂ and then 2.5% 2M ammonia in methanol; 97.5% CH ₂ Cl ₂ to give a yellow brown solid. (108 mg, 55% yield) ¹ H NMR (DMSO- d ₆ ) δ 7.67 (d, J = 3.0 Hz, 1H), 7.54 (d, J = 5.1 Hz, 1H), 7.07 (dd, J = 3.9, 5.1 Hz), 6.62-6.47 (m, 3H), 6.21 (s, 2H), 3.57-3.50 (m, 1H), 3.11 (t, J = 5.4 Hz, 2H), 2.63 (t, J = 6.3 Hz, 2H) ), 2.28 (s, 3H), 2.24-2.20 (m, 1H), 1.98-1.92 (m, 2H), 1.82-1.77 (m, 2H), 1.70-1.65 (m, 2H), 1.59-1.47 (m , 2H), 1.24-1.11 (m, 2H). ESI-MS (m/z, %): 369 (MH ⁺ , 82), 338 (100), 258 (21), 185 (50), 148 (64), 140 (46); For C ₂₁ H ₂₉ N ₄ S(MH ⁺ ): 369.2107, observed: 369.2104; HPLC purity: 95.3%.

Example 75

6-nitro-1-(3-(pyrrolidin-1-yl)propyl)-3,4-dihydroquinolin-2(1H)-one:

6-Nitro-1-(3-(pyrrolidin-1-yl)propyl)-3,4-dihydroquinolin-2(1H)-one (516 mg, 1.701 mmol, 91%) with stirring The yield) and a suspension of potassium carbonate (1286 mg, 9.30 mmol) in acetonitrile (10 ml) were added to the syringe, and pyrrolidine (0.777 ml, 9.30 mmol). The reaction vessel was sealed and heated at 80 °C overnight. The reaction mixture was then cooled to room temperature, diluted with water and extracted with dichloromethane (3x). The combined organic phases were dried, filtered and concentrated, then purified eluting with EtOAc EtOAc (EtOAc) 1-(3-(Pyrrolidin-1-yl)propyl)-3,4-dihydroquinolin-2(1H)-one (516 mg, 1.701 mmol, 91% yield). ¹ H NMR (DMSO- d ₆ ) δ 8.15-8.10 (m, 2H), 7.39 (d, J = 8.7 Hz, 1H), 3.97 (t, J = 7.4 Hz, 2H), 3.00 (t, J = 7.5) Hz, 1H), 2.64-2.59 (m, 2H), 2.44-2.39 (m, 6H), 1.72-1.65 (m, 6H)

6-nitro-1-(3-(pyrrolidin-1-yl)propyl)-1,2,3,4-tetrahydroquinoline:

6-Nitro-1-(3-(pyrrolidin-1-yl)propyl)-3,4-dihydroquinolin-2(1H)-one (500 mg, 1.648 mmol) was conjugated to borane tetrahydrofuran A solution of 1M in THF (16.500 mL, 16.50 mmol) was stirred at 60 ° C overnight. The reaction mixture was then cooled to 0 ° C and quenched with methanol. The resulting solution was concentrated, and the residue was evaporated mjjjl This mixture was then neutralized with 1N sodium hydroxide and then extracted with dichloromethane (3×). The combined organic phases were dried, filtered and concentrated and then purified eluting with EtOAc EtOAc EtOAc EtOAc EtOAc 1-(3-(Pyrrolidin-1-yl)propyl)-1,2,3,4-tetrahydroquinoline (270 mg, 0.933 mmol, 56.6% yield). ¹ H NMR (DMSO- d ₆ ) δ 7.87 (dd, J = 9.3, 2.7 Hz, 1H), 7.77 (d, J = 2.7 Hz, 1H), 6.70 (d, J = 9.3 Hz, 1H), 3.46- 3.38 (m, 4H), 2.74 (t, J = 6 Hz, 2H), 2.43 - 2.38 (m, 6H), 1.86-1.82 (m, 2H), 1.74-1.67 (m, 6H)

1-(3-(pyrrolidin-1-yl)propyl)-1,2,3,4-tetrahydroquinolin-6-amine:

6-Nitro-1-(3-(pyrrolidin-1-yl)propyl)-1,2,3,4-tetrahydroquinoline (270 mg, 0.933 mmol) in ethanol (5 ml) And a solution of tetrahydrofuran (5.00 ml), palladium on activated carbon, 10 wt.% (99 mg, 0.093 mmol). The resulting suspension was stirred under a hydrogen atmosphere (balloon pressure) and monitored by TLC. After 2 hours, the reaction mixture was filtered through a pad of celite and then washed with methanol. The filtrate was then concentrated to give 1-(3-(pyrrolidin-1-yl)propyl)-1,2,3,4-tetrahydroquinolin-6-amine (238 mg, 0.918 mmol, 98% yield). Dark oil.

N- (1-(3-(Pyrrolidin-1-yl)propyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboxyindoleimine:

1-(3-(pyrrolidin-1-yl)propyl)-1,2,3,4-tetrahydroquinolin-6-amine (115 mg, 0.443 mmol) in EtOAc (6 mL) The solution was added with methylthiophene-2-carboquinone thiocarboxylate hydrogen iodide (253 mg, 0.887 mmol) under argon. The reaction mixture was stirred at room temperature overnight. The mixture was then diluted with water and sodium carbonate and extracted with dichloromethane (3×). The combined organic phases are dried, filtered and concentrated, then chromatographed on ethyl acetate, and then 5-10% (2M NH3 in methanol) in dichloromethane as eluent to obtain the desired N- ( 1-(3-(pyrrolidin-1-yl)propyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboxyindoleimide decylamine (119 mg, 0.323 mmol, 72.8% production). ¹ H NMR (DMSO- d ₆ ) δ 7.67 (d, J = 3.6 Hz, 1H), 7.55 (d, J = 5 Hz, 1H), 7.06 (dd, J = 5, 3.6 Hz, 1H), 6.58 (brs) , 2H), 6.48 (s, 1H), 6.27 (brs, 2H), 3.26-3.17 (m, 4H), 2.66 (t, J = 6.3 Hz, 2H), 2.45-2.40 (m, 6H), 1.89- 1.81 (m, 2H), 1.70-1.62 (m, 6H). ESI-MS (m/z, %) 369 (MH+, 47), 185 (100). ESI-HRMS calcd for C21H29N4S (MH+), found: 369.2122, observed: 369.2107. HPLC purity: >95%.

Example 76

1-(3-(pyrrolidin-1-yl)propyl)-1,2,3,4-tetrahydroquinolin-6-amine:

See of Example 75

5-methyl-N-(1-(3-(pyrrolidin-1-yl)propyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboximine Guanamine:

1-(3-(pyrrolidin-1-yl)propyl)-1,2,3,4-tetrahydroquinolin-6-amine (115 mg, 0.443 mmol) in EtOAc (6 mL) To the solution, methyl 5-methylthiophene-2-carbomine imine thiocarboxylate hydrogen iodide (265 mg, 0.887 mmol) was added. The resulting suspension was stirred at room temperature overnight. This mixture was then diluted with water and sodium carbonate and extracted with dichloromethane. The combined organics were dried, filtered and concentrated, then purified eluting with EtOAc EtOAc EtOAc EtOAc N- (1-(3-(pyrrolidin-1-yl)propyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboxyindoleimide (98 mg, 0.256 mmol, 57.8% yield). ¹ H NMR (DMSO- d ₆ ) δ 7.45 (d, J = 3.3 Hz, 1H), 6.74 (d, J = 2.4 Hz, 1H), 6.53 (m, 2H), 6.45 (s, 1H), 6.13 ( Brs, 2H), 3.26-3.16 (m, 4H), 2.68-2.63 (m, 2H), 2.43-2.39 (m, 6H), 2.41 (s, 3H), 1.86-1.82 (m, 2H), 1.68- 1.64 (m, 6H). ESI-MS (m/z, %) 383 (MH+, 39), 272 (49), 192 (100). ESI-HRMS calculated for C22H31N4S (MH+), calculated: 383.2264, observed:

Example 77:

The data was obtained using the method of Examples 19a-b.

Rodent data is in brackets.

Example 78. Sciatic sheath (Cuff) model of neuropathic pain:

In humans (or other species), persistent pain may occur as a result of postherpetic neuralgia, diabetes, cancer or trauma, characterized by spontaneous pain and tenderness (pain or pain caused by normal, harmless mechanical stimuli) . Several theories have been proposed to explain the underlying mechanisms of peripheral neuropathic pain, including changes in the central nervous system, especially the spinal dorsal horn, including mechanisms of altered signaling mechanisms, central sensitization, and reduced suppression mechanisms (GM). Pitcher and JL Henry, Exp. Neurol. 2004, 186, 173-197 and references therein). Relative to the central mechanism, in peripheral neuropathy, modifying the peripheral sensory pathway (eg, altering the gene expression of large-sized non-painful neurons) causes a dilated peripheral recipient region that slowly decays after discharge in spinal neurons, It also causes neuropathic pain.

The rat sciatic sheath model (Mosconi and Kruger, 1996, Pain 64, 37-57) involves implanting a plastic sheath in the sciatic nerve, causing painful neurological diseases several days after surgery, and after innocuous peripheral mechanical stimulation, Pain is induced after spinal nerve discharge (GMPitcher and JL Henry). Mechanical tenderness was measured on the ipsilateral paw using a calibrated von Frey hair test. The single acute administration of this drug (intraperitoneal administration) reversed the post-sheath pain threshold for mechanical stimulation towards a normal threshold level.

This study used a sheath model (Mosconi T, Kruger L. Fixed-diameter polyethylene cuffs applied to the rat sciatic nerve induce a painful neuropathy: ultrastructural morphometric analysis oFaxonal alterations. Pain 64: 37-57, 1996) to examine test compounds. 11 The therapeutic effect of the series of behavioral endpoints in rats.

Mechanical tenderness - von Frey Hair

The lab consists of a 30 x 30 x 30 cm Plexiglas box with a transparent Plexiglas floor. The ground consisted of 0.5 cm diameter holes, 1.5 cm apart, and placed on a mirror to allow for unobstructed viewing of the rat's paws. Animals were placed in this test chamber and allowed to acclimate for 30 minutes prior to testing. Frey's filaments (Stoelting Co., Illinois, USA) were applied to the soft tissue of the posterior paw to determine the retraction threshold. The first filament applied was corresponding to a force of 4.31 g. If a negative reaction (no movement) is observed, a greater force is applied to the filament, and if a positive reaction is observed (claw is retracted from the platform), then Filaments of lesser strength. Each filament was applied 3 times at 3 second intervals. The 50% response threshold was calculated according to the response pattern observations (described by Chaplan et al. 1994). The maximum score may be 15g and the minimum is 0.25g.

Baseline values were taken with Frey's hair before model induction. The rats were then acclimated to the laboratory and at least 3 days of readings were taken against the baseline prior to any surgery. After the surgery, the assessment was conducted to develop any mechanical sensitivity and to conduct Frey's hair test.

Open-closed lifting platform

The test device consists of a long, narrow, rectangular platform (79 cm x 17.5 cm or 31 in. x 7 in.), which is off-ground (1.1 m. or 43 in.). Half of the platform is covered with 3 walls and a ceiling, and the other half is open. There are no obstructions in the two compartments, so the rat can move freely between them. A typical test is to place the rat on the open platform and observe how much time it takes in each compartment during the 10 minute observation period. This test is usually carried out once at room temperature for adaptation purposes. Normal rats will prefer to stay in a closed chamber. The test was performed at time 2, when the closed compartment was 1 °C - 10 °C to study the temperature and surrounding preferences of rats caused by various pain models. This test was carried out at 0 ° C in the closed compartment at the 2nd hour. Therefore, the preferred chamber becomes a disgusting situation. A normal rat still prefers a closed cold chamber more than an open space. This result is different for rats that have developed cold sensitivity. Therefore, the time spent in each chamber was recorded, and the differences before and after the surgery reflected the pain sensitivity. This test design determines and measures any cold oversensitivity at the foot. People with neuropathic pain often feel cold and painful.

The animals were placed in a box of approximately 12 x 12 x 12 inches. The bottom was filled with an ice-salt mixture and the metal plate was placed on the mixture. Record the time of lifting or licking as a reverse measure of cold sensitivity.

This test will be carried out for about 2 minutes. Post-test treatment - Wrap the foot in a soft cloth or paper towel and return the animal to its usual cage for 5 minutes. The wide limit can be added to the time of transmission and adaptation to the next test device.

Model induction

A method of inducing peripheral neuropathy is performed by implanting a single sheath around the sciatic nerve, modified from the method described by Mosconi and Kruger (1996), using 2 to 4 sheaths. Rats were anesthetized with ketamine (5 mg/100 g) and xylazine (0.5 mg/100 g) in combination with intraperitoneal injection. After cutting the blunt end of the overlying muscle, the left sciatic nerve is exposed and separated from the surrounding tissue. A length of 2 mm polyethylene (PE-90) tube (Intramedic PE-90, Clay Adams, Division o FBecton Dickinson, Parsippany, NJ) was longitudinally fitted around the nerve. The muscles are then sutured and the skin is closed with a suture clip. An antibiotic ointment (Nitrofurazone 0.2%) was applied to the wound and 0.03 ml of antibiotic Tribrissen 24% (trimethoprim-sulfadiazine) was intraperitoneally injected. The animals were placed under a heat lamp until they recovered from anesthesia and returned to the original cage.

The results of test compound 11 are shown in Figures 14 to 17. Therefore, the nNOS inhibitor of the present invention is useful for treating neuropathic pain associated with peripheral neuropathy.

After injury to the sciatic nerve implanted in the sheath, the animals showed tactile hypersensitivity and remained stable for at least 4 weeks of induction. Example 11 was administered (abdominal 30 mg/kg) and this tactile hypersensitivity was reversed 2 and 4 hours after the first injection. The pre-injection reading of the second drug administration day showed a continuous reversal of the tactile hypersensitivity - that is, the first dose had a full potential effect. After administration of Example 11, there was no adverse effect on tactile sensitivity.

Cold tenderness is associated with peripheral neuropathy and neuropathic pain (Seung Keun Back et. al. Neuroscience Lett. 2004, 368, 341-344). Rats in the naive (Naïve) control group were shown to have a paw lift (4 ± 2 °C) in the cold plate test, in which the sciatic nerve was transplanted with a sheathed rat, which averaged 10 minutes during the 4 test days. There are an average of 18 claw lifts. Example 11 (abdominal 30 mg/kg) was administered daily to reduce paw lift to an average of about 9 paw lifts during the 10 minute test period (Figure 16).

After the posterior leg was implanted in the ischial sheath, the difference in the weight of the hind paw (before administration of the drug on each day) showed the preference placed on the opposite hind paw - that is, avoiding the paw standing in the neuropathy. On the first day of the application of Example 11, the weight was placed toward the average distribution of the two hind paws. The effect of Example 11 was observed at 2 hours and 4 hours after administration, and 24 hours after the first dose, the hind paw weight distribution showed a preference for the contralateral hind paw. A few days after the application, the weight was placed offset toward the average distribution. (Figure 17)

Example 79

Irritable bowel svndrome (IBS), characterized by abdominal pain and flatulence, is often difficult to treat. Rectal perfusion of butyrate, providing one A clinically relevant rat model of non-inflammatory colonic oversensitivity (Bourdu et. al. 2005) (Figure 18). The lumbar hypersensitivity of the reference in the colon hypersensitivity model was quantified by applying Freire's hair to the rat lumbar dermis (Bourdu S, Gastroenterology. 2005 Jun; 128(7)). The butyrate is then administered rectally, causing tactile hypersensitivity to the location of the abdomen, which can be reversed by administration of a compound of the invention. Figure 19 shows the effect of administration of Compound 11 on visceral pain.

Example 80

Figure 7 shows a schematic representation of the painful Porreca model (US 2008/0031822).

Animals. Male Sprague Dawley rats (275-300 g) were purchased from Harlan Sprague Dawley (Indianapolis, IN). Animals are given food and water. Animals were maintained at 12 hours light (7am to 7pm) and 12 hour dark cycle (7pm to 7am). All procedures are in accordance with the policies and recommendations of the International Association for the Study of Pain and the National Institutes of Health guidelines, and laboratory animals are approved by the Animal Care and Use Committee oFthe University oFArizona.

Surgical preparation

Migraine cannulation: Male Sprague Dawley rats were anesthetized with ketamine/xylazine (80 mg/kg, ip), and the head was depilated using a rodent scissors (Oster Golden A5 w/size 50 blade) and cut The area is cleaned with betadine and 70% ethanol. The animals were placed in a stereotactic device (Stoelting Model 51600) and a heating pad was placed under the animals to maintain a core temperature of 37 °C. In the cut and cleaned area of the head, use a #10 blade scalpel, draw a 2 cm incision, and use sterile cotton gauze to clean any bleeding. Find the suture position of the bregma and midline bone as a reference, and use a hand drill to open a small hole with a diameter of 1 mm without destroying the dura mater but deep enough to expose the dura mater. Two additional holes (1 mm in diameter) of 4 to 5 mm are opened in the front part to install stainless steel screws (Small Parts #A-MPX-080-3F), and the empty tube is fixed, and the inflammatory soup is passed through the empty tube. Juice is delivered to induce experimental migraine. A modified intracerebroventricular (ICV) cannula (Plastics One #C313G) was placed in the well without penetrating or passing through the dura mater. The ICV cannula was cut from the bottom of the plastic wire to a length of 1 mm by using a Dremel mototool and a file to remove any steel burrs. Once the modified migraine cannula is positioned, dental acrylic is placed around the migraine cannula and securely mounted with stainless steel screws to secure the cannula. Once the dental acrylic is dry (ie, after 10-15 minutes), the cannula cap is secured to the top to prevent contaminants from entering the cannula and the skin is sewn back using a 3-0 suture. Animals were given antibiotic injection (Amikacin C, 5 mg/kg, im) and removed from the stereotactic frame to wake up from anesthesia on a heating pad. The animals were placed in a clean, separate squirrel cage for a 5-day recovery period.

Injection. Subcutaneous injection: Subcutaneous injection (sc) is performed by manually holding the animal and inserting a caliber 25 disposable needle into the abdomen of the animal in a disposable 1 cc syringe to ensure that the needle is still between the muscle and skin of the animal. The injected compound was administered over a period of 5 seconds and was positive by creating an outer pouch at the skin of the injection site. Oral delivery was performed using a caliber 18 gavage needle attached to a 1 cc syringe.

Migraine cannula injection: The injection cannula (Plastics One, C313I cut into a modified ICV cannula) was attached to a 25:1 Hamilton syringe (1702SN) using a tygon tube (Cole-Palmer, 95601-14) A 10:1 inflammatory mediator solution was injected into the dura mater.

Behavioral testing. Prior to the day of migraine surgery, naïve animals were placed in a plexiglass chamber (30 cm LX 15 cm WX 20 cm H) suspended in a metal mesh (1 cm ² ) and allowed to acclimate to the test chamber for 30 minutes.

Rat paw perception threshold for harmless tactile stimulation

The paw withdrawal threshold for tactile stimulation is determined by the detection in response to the corrected Frei's filament (Stoelting, 58011). Frey's filaments were applied perpendicular to the plane of the hind paw of the animal until slightly bent for 3 to 6 seconds. The claws are quickly withdrawn, representing a positive reaction. The 50% paw withdrawal threshold is determined by the non-parametric method of Dixon (1980). An initial probe equal to 2.00 g is applied, and if the reaction is negative, an increase in stimulation is increased, otherwise in the case of a positive reaction, an increase is decreased. Stimulation increases sequentially until a positive response is obtained and then decreases until a negative response is observed. Repeat this "up-down" method until the behavior determines 3 changes. The pattern of positive and negative reactions is tabulated. The 50% claw withdrawal threshold is determined by (10 ^[Xf+k] ) / 10,000, where XF = the value of the last Freire filament, k = the Dixon value of the positive/negative pattern, and M = the stimulus The average (logarithmic) is poor. Only naive animals with a baseline of 11 to 15 g were used for the experiment. 15g is taken as the maximum cutoff value. Five days after migraine surgery, the paw withdrawal threshold was again tested using the same domestication and Frey's procedure as above. The data was converted to % "anti-tender" using % activity = 100 x (post-migraine value - baseline value) / (15 g - baseline value). Only the values before the migraine surgery, the tactile hypersensitivity proved no difference in the animals, used in all studies.

After establishing the baseline paw withdrawal threshold, individual animals were removed from the test chamber and the migraine cannula cap removed, and the animal was injected with an inflamed vehicle mixture (1 mM tissue) over 5 to 10 seconds via the migraine cannula. amine, 1mM 5-HT [serotonin], ImM kallikrein (Bradykinin), 1mM PGE ₂₎ or a carrier volume of lOuL, this inflammation media (IM) mixture, freshly prepared each day of the experiment in the system. The migraine cannula cap was replaced and the individual animals were returned to the corresponding laboratory and the paw withdrawal threshold was measured at 1 hour intervals over a 6 hour period. Data were converted to % "anti-tender" with % activity = 100 x (post-IM value - pre-IM baseline value) / (15 g - pre-IM baseline value).

The data for the selected compounds of the invention obtained using this mode are shown in Figures 8 (Compound 23) and 13 (Compound 28). Inflamed broth (IS) is applied to the meninges, causing a reduction in the hind paw withdrawal threshold when stimulated with Frey's filaments. Five minutes before the addition of the broth, Sumatriptan succinate (1 mg/kg subcutaneous injection) was administered for 5 minutes, and 2 hours after the administration of IS, it was measured to prevent the formation of hind paw tenderness. Similarly, 15 minutes before IS, a non-selective NOS inhibitor L-NMMA (10 mg/kg intravenously) or 23 and 28 (30 mg/kg po) was administered for 15 minutes, and reversal resulted in hind paw tenderness. Therefore, non-selective NOS inhibitors, such as L-NMMA, or more selective nNOS inhibitors (eg, compounds 23 and 28 ), should be useful in the treatment of migraine.

Other embodiments

Although the present invention has been described with reference to the specific embodiments, it is understood that the invention is not limited to the embodiments disclosed herein. On the contrary, the invention is intended to cover any modifications and equivalents thereof

All of the publications, patents, and patent applications mentioned in this specification are hereby incorporated by reference in their entirety in their entirety in the the the the the the When a term is used in this application to be different from the terminology used herein as a reference, the definitions provided herein will control.

Other embodiments are within the scope of the patent application.

Figure 1 is an overview of the Chung model of thermal hyperalgesia.

Figure 2 is a graph of the dose response of the compound of Example 11 in hyperalgesia in the Chung model.

Figure 3 is a graph showing the effect of the compound of Example 3 on hyperalgesia in the Chung model.

Figure 4 is a graph showing the effect of the compound of Example 23 on hyperalgesia in the Chung model.

Figure 5 is a summary of the Chung model of tactile oversensitivity.

Figure 6 is a graph showing the effect of the compound of Example 23 on tenderness in the Chung model.

Figure 7 is a summary of the Porreca model of tactile oversensitivity.

Figure 8 is a graph showing the effect of the compound of Example 23 on tenderness in the Porreca model.

Figure 9 is a graph showing the effect of the compound of Example 37 on hyperalgesia in the Chung model.

Figure 10 is a graph showing the effect of the compound of Example 47 on hyperalgesia in the Chung model.

Figure 11 is a graph showing the effect of the compound of Example 54 on hyperalgesia in the Chung model.

Figure 12 is a graph showing the effect of the compound of Example 28 on hyperalgesia in the Chung model.

Figure 13 is a graph showing the effect of the compound of Example 28 on tenderness in the Porreca model.

Figure 14 shows the effect of a single dose of Compound 11 on tenderness in a model of the sciatic nerve sheath.

Figure 15 shows the effect of multiple doses of Compound 11 on tenderness in a model of the sciatic nerve sheath.

Figure 16 shows the effect of Compound 11 on the frequency of paw lift in a sciatic sheath model.

Figure 17 shows the effect of Compound 11 on the weight of the hind leg in the sciatic sheath model.

Figure 18 is a summary of one of the models for visceral pain.

Figure 19 is the effect of Compound 11 on a visceral pain rat model.

Claims (88)

a compound of the following formula (I), or a pharmaceutically acceptable salt thereof: Wherein Q is (CHR ⁶ ) _1-3 ; R ¹ and each R ^{6 are} independently H, optionally substituted C _1-6 alkyl, optionally substituted C _1-4 alkaryl, optionally substituted a C _1-4 alkane heterocyclyl, a randomly substituted C _2-9 heterocyclyl, or a randomly substituted C _3-8 cycloalkyl; R ² is H, Hal, optionally substituted C _1-6 alkane a randomly substituted C _1-6 alkaryl group, a hydroxy group, a randomly substituted C _1-6 alkoxy group, or a randomly substituted C _1-6 thioalkoxy group; R ³ is H, Hal, optionally Substituted C _1-6 alkyl, optionally substituted C _1-6 alkaryl, hydroxy, optionally substituted C _1-6 alkoxy, optionally substituted C _1-6 thioalkoxy, or (CH ₂ ) _r2 NHC(NH)R ^2A ; wherein r 2 is an integer from 0 to 2, R ^2A is C _1-6 alkyl, optionally substituted C _6-10 aryl, optionally substituted C _2-9 Heterocyclyl, optionally substituted C _1-4 alkane heterocyclyl, optionally substituted C _1-4 sulfane aryl, optionally substituted aryl fluorenyl, optionally substituted C _1-4 sulfane heterocycle a group, or an amine group; each of R ⁴ and R ^{5 is} independently H, Hal, or (CH ₂ ) _{r 2} NHC(NH)R ^2A ; wherein Y ¹ and Y ^{2 are} each H, or both Y ¹ and Y ² are =O, or Y ¹ and Y ² alone Site is H, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 alkaryl, hydroxy, optionally substituted C _1-6 alkoxy, or optionally substituted C _1-6 a thioalkoxy group; wherein only one of R ³ , R ⁴ and R ⁵ is (CH ₂ ) _{r 2} NHC(NH)R ^2A . The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Q is (CHR ⁶ ) _1-3 ; R ¹ and each R ^{6 are} independently H, optionally substituted C _{1 a -6} alkyl group, a randomly substituted C _1-4 alkaryl group, a randomly substituted C _1-4 alkylene group, or a randomly substituted C _2-9 heterocyclic group; R ² is H, Hal, Optionally substituted C _1-6 alkyl, optionally substituted C _1-6 alkaryl; R ³ is H, Hal, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 alkane Aryl; each R ⁴ and R ^{5 are} independently H or (CH ₂ ) _{r 2} NHC(NH)R ^2A ; wherein Y ¹ and Y ^{2 are} each H, or both Y ¹ and Y ² are =O; wherein R ⁴ And one of R ⁵ but not H at the same time. The compound of claim 1 or 2, wherein Y ¹ and Y ² are both =0, and Q is (CHR ⁶ ) ₂ . The compound of claim 1 or 2, wherein Y ¹ and Y ^{2 are} each H and Q is (CHR ⁶ ) ₂ . The compound of claim 1 or 2, wherein Y ¹ and Y ² are both =0 and Q is CHR ⁶ . The compound of claim 1 or 2 wherein Y ¹ and Y ^{2 are} each H and Q is CHR ⁶ . The compound of claim 1 or 2, wherein Y ¹ and Y ² are both =0 and Q is (CHR ⁶ ) ₃ . A compound according to claim 1 or 2 wherein Y ¹ and Y ^{2 are} each H and Q is (CHR ⁶ ) ₃ . The compound of any one of claims 1 to 8, wherein R ⁴ or R ⁵ has the formula: ; and where Z is R ^2A . The compound of claim 9, wherein R ^2A has the formula: And each X ¹ , X ² , X ⁴ and X ^{5 are} independently selected from: O, S, NR ⁷ , N, or CR ⁸ ; X ^{3 is} selected from: N or C; R ⁷ is H or optionally Substituted C _1-6 alkyl; R ⁸ is H, Hal, optionally substituted C _1-6 alkyl, hydroxy, optionally substituted C _1-6 alkoxy, or optionally substituted C _{1- 6} thioalkoxy; and wherein at least one of X ¹ , X ² , X ⁴ and X ^{5 is} not CR ⁸ . The compound of claim 10, wherein R ^2A has the formula: And each of X ¹ and X ^{2 is} independently selected from: O, S, NH, N, or CH; and wherein at least one of X ¹ and X ^{2 is} not CH. The compound of any one of claims 1 to 8 wherein R ² or R ³ has the formula: ; and where Z is R ^2A . The compound of claim 12, wherein R ^2A has the formula: And each X ¹ , X ² , X ⁴ and X ^{5 are} independently selected from: O, S, NR ⁷ , N, or CR ⁸ ; X ^{3 is} selected from: N or C; R ⁷ is H or optionally Substituted C _1-6 alkyl; R ⁸ is H, Hal, optionally substituted C _1-6 alkyl, hydroxy, optionally substituted C _1-6 alkoxy, or optionally substituted C _1-6 a thioalkoxy group; and at least one of X ¹ , X ² , X ⁴ and X ^{5 is} not CR ⁸ . The compound of claim 13, wherein R ^2A has the formula: And each of X ¹ and X ^{2 is} independently selected from: O, S, NH, N, or CH; and wherein at least one of X ¹ and X ^{2 is} not CH. The compound of claim 11 or 14, wherein X ¹ is CH and X ² is S. A compound wherein the compound has the formula: A pharmaceutically acceptable salt. A pharmaceutical composition comprising a compound of any one of the compounds of claims 1 to 16 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. Use of a compound of any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof for the treatment or prevention of nitric oxide synthase (NOS) in a mammal Symptomatic drugs. The use of claim 18, wherein the mammal is a human. For use as described in claim 18, wherein the symptoms are: migraine (with or without aura), chronic tension headache (CTTH), migraine with tenderness, overdose headache, neuropathic pain , AIDS-related neuropathic pain, chronic headache, central post-stroke pain (CPSP), drug-induced hyperalgesia, or tenderness, acute pain, chronic pain, diabetic neuropathy, trigeminal neuralgia, chemotherapy-induced neuropathy Pain, bone cancer pain, chemical dependence or drug addiction, CNS disorders, neurodegenerative or neurological damage, cardiovascular related symptoms, diabetic nephropathy, inflammatory disease, or gastrointestinal disorders. The use according to claim 20, wherein the drug causes hyperalgesia or tenderness, which is hyperalgesia or tenderness caused by opioid or hyperalgesia or tenderness caused by 5-HT _1D/1B synergist. The use according to claim 20, wherein the neuropathic pain caused by the chemotherapy is caused by paclitaxel, cis-Platin, or Doxorubicin. The use of the scope of claim 20, wherein the chemical dependence or addiction is cocaine addiction, nicotine addiction, methamphetamine-induced neurotoxicity, alcohol tolerance, dependence or withdrawal, Or tolerance, dependence, hyperalgesia or withdrawal caused by opioids. The use of claim 20, wherein the CNS disorder is epilepsy, anxiety, depression, attention deficit hyperactivity disorder (ADHD), psychopathy or dementia. The use according to claim 20, wherein the neurodegenerative disease or nerve damage is acute spinal cord injury, AIDS-related dementia, Parkinson's disease, Alzheimer's disease. , ALS, Hunter's disease, multiple sclerosis, neurotoxicity or head trauma. The use of the scope of claim 20, wherein the cardiovascular-related symptoms are stroke, coronary artery bypass graft (CABG)-related neurological damage, hypothermic cardiac arrest (HCA), post-stroke pain, and cardiac shock. , reperfusion injury or vascular dementia. The use of claim 20, wherein the inflammatory disease is osteoarthritis or inflammation of a neuron. The use according to claim 20, wherein the gastrointestinal disorder is ileostomy-associated diarrhea, pour-on syndrome, or visceral pain. For example, the application of the scope of claim 18, wherein the symptoms are stroke, reperfusion injury, head trauma, migraine (with or without aura), migraine with tenderness, chronic tension headache, neuropathic pain, Central post-stroke pain (CPSP), or chronic pain. The use of claim 18, wherein the symptom is central post-stroke pain (CPSP). The use of claim 18, wherein the use further comprises administering a type of opium to the mammal. The use according to claim 31, wherein the opium is alfentanil, butorphanol, buprenorphine, dextromoramide, dezocine, dextroampheparin ( Dextropropoxyphene), codeine, codeine, diphenoxylate, etorphine, fentanyl, hydrocodone, hydromorphone, Ketobemidone, levorphanol, levomethadone, meptazinol, methadone, morphine, morphine-6-glucoside, nalbuphine ), naloxone, oxycodone, oxymorphone, pentazocine, pethidine, piritramide, propoxyphene, Remifentanil, sand Sulfentanyl, Tilidine, or tramadol. The use of claim 18, wherein the use further comprises administering an antidepressant to the mammal. The use of claim 33, wherein the antidepressant is a selective serotonin recovery inhibitor. The use according to claim 34, wherein the selective serotonin recovery inhibitor is: cialopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, or sertraline. The use of claim 33, wherein the antidepressant is a norepinephrine recovery inhibitor. The method of claim 36, wherein the norepinephrine recovery inhibitor is: amitriptyline, desmethylamitriptyline, clomipramine, doxepin, imipramine, imipramine oxide, trimipramine, adinazolam, amiltriptylinoxide, amoxapine, desipramine, maprotiline, Nortriptyline, Protriptyline, amineptine, butriptyline, demexiptiline, dibenzepin, dimetacrine, dothiepin, fluacizine, iprindole, lofepramine, melitracen, metapramine, norclomipramine, Noxiptilin, opipramol, perlapine, pizotyline, propizepine, quinupramine, Reboxetine, or tianeptine. The use of claim 33, wherein the antidepressant is a noradrenaline/norepinephrine recovery inhibitor. The use according to claim 38, wherein the selective norepinephrine/norepinephrine recovery inhibitor is atomoxetine, bupropion, Reboxetine, or tomoxetine. The use of claim 33, wherein the antidepressant is a dual serotonin/norepinephrine recovery inhibitor. The use of claim 40, wherein the dual serotonin/norepinephrine recovery inhibitor is duloxetine, milnacipran, mirtazapine, Nefazodone, or venlafaxine. The use of claim 33, wherein the antidepressant is a monoamine oxidase inhibitor. The use according to claim 42, wherein the monoamine oxidase inhibitor is amiflamine, iproniazid, isocarboxazid, moclobemide, pargyline, phenelzine, tranylcypromine, or vanoxerine. The use of claim 33, wherein the antidepressant is a reversible monoamine oxidase type A inhibitor. The use according to claim 44, wherein the reversible monoamine oxidase type A inhibitor is bazinaprine, befloxatone, brofaromine, cimoxatone, or clorgyline. The use of claim 33, wherein the antidepressant is a paraffin. The use of the scope of claim 46, wherein the cyclamate is amitriptyline, clomipramine, desipramine, doxepin, imipramine, magrotiline, nortryptyline, protriptyline, or trimipramine. The use according to claim 33, wherein the antidepressant is adinazolam, alaproclate, amineptine, amitriptyline/chlordiazepoxide combination, atipamezole, azamaneserin, bazinaprine, befuraline, bifemelane, binodaline, bipenamol, brofaromine, caroxazone, cericlamine, cianopramine , cimoxatone, citalopram, clemprol, clavoxamine, dazepinil, deanol, demexiptiline, dibenzepin, dothiepin, droxidopa, enefexine, estazolam, etoperidone, femoxetine, fengabine, fezolamine, fluotracen, idazoxan, indalpine, indeloxazine, iprindole, levoprotiline, lithium, litoxetine, lofepramine , medifoxamine, metapramine, metalindole, mianserin, milnacipran, minaprine, mirtazapine, montirelin, Nebracetam, Nefopam, Nialamide, Nomifensine, Norfluoxetine, orotirelin, oxaflozane, pinazepam, pirlindole, pizotyline, Ritanserin, Rolipram, sercloremine, setiptiline, sibutramine, sulbutiamine, sulpiride , teniloxazine, thozalinone, thyroliberin, tianep Tine, tiflucarbine, trazodone, tofenacin, tofisopam, toloxatone, tomoxetine, veralipride, viloxazine, viqualine, zimelidine, or zometapine. The use of claim 18, wherein the use further comprises administering an anti-epileptic drug to the mammal. The use according to claim 49, wherein the anti-epileptic drug is carbamazepine, flupirtine, gabapentin, lamotrigine, oxcarbazepine, phenytoin, retigabine, topiramate, or valproate. The use of claim 18, wherein the use further comprises administering to the mammal a non-steroidal anti-inflammatory drug (NSAID) or acetaminophen. The use according to claim 51, wherein the NSAID is: acemetacin, aspirin, celecoxib, deracoxib, diclofenac, diflunisal, ethenzamide, etofenamate, etoricoxib, fenoprofen, flufenamic acid, flurbiprofen, lonazolac, lornoxicam, ibuprofen, indomethacin, Isoxicam, kebuzone, ketoprofen, ketorolac, Naproxen, Nabumetone, Niflumic acid, sulindac, tolmetin, piroxicam, meclofenamic acid, mefenamic acid, meloxicam, metamizol, mofebutazone, oxyphenbutazone, parecoxib, phenidone, phenylbutazone, piroxicam, propacetamol, propyphenazone, rofecoxib, salicylamide , suprofen, tiaprofenic acid, tenoxicam, valdecoxib, 4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide, N-[2-(cyclohexyloxy)- 4-nitrophenyl]methanesulfonamide, 2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methylbutoxy)-5-[4-(methylsulfonate) Mercapto)phenyl]-3(2H)- Pyridazinone, or 2-(3,5-difluorophenyl)-3-[4-(methylsulfonyl)phenyl]-2-cyclopenten-1-one). The use of claim 18, wherein the use further comprises administering an antiarrhythmic drug to the mammal. The use of claim 18, wherein the use further comprises administering to the mammal a GABA-B antagonist. The use of claim 18, wherein the use further comprises administering to the mammal an alpha-2-adrenergic receptor synergist. The use of claim 18, wherein the use further comprises administering to the mammal a serotonin 5HT _1B/1D synergist. The use of claim 56, wherein the serotonin 5HT _1B/1D synergist is: eletriptan, frovatriptan, Naratriptan, Rizatriptan, sumatriptan, donitriptan, or zolmitriptan. The use of claim 18, wherein the use further comprises administering to the mammal an N-methyl-D-aspartate antagonist or a glutamate receptor antagonist. The use according to claim 58 wherein the N-methyl-D-aspartate antagonist or glutamate receptor antagonist is amantadine; aptiganel; besonprodil; budipine; conantokin G; Dexanabinol;dextromethorphan;dextropropoxyphene;felbamate;fluorofelbamate;gacyclidine;glycine;ipenoxazone;kaitocephalin;ketamine;ketobemidone;lanicemine;licostinel;midafotel;memantine;D-methadone;D-morphine;milnacipran;neramexane;orphenadrine;remacemide;sulfazocine;(+ /-)-1-methyl-1,2-diphenylethylamine monohydrochloride;topiramate;(α R)-α-amino-5-chloro-1-(phosphomethyl)-1H-benzimidazole-2-propionic acid; -aminocyclopentane-carboxylic acid; [5-(aminomethyl)-2-[[[(5 S )-9-chloro-2,3,6,7-tetrahydro-2,3-di Sideoxy-1H-,5H-pyrido[1,2,3-de]quinoxalin-5-yl]ethenyl]amino]phenoxy]-acetic acid; α-amino-2-( 2-phosphoethyl)-cyclohexanepropionic acid; α-amino-4-(phosphomethyl)-phenylacetic acid; (3E)-2-amino-4-(phosphomethyl)-3-heptene Acid; 3-[(1E)-2-carboxy-2-phenylvinyl]-4,6-dichloro-1H-indole-2- Acid; 8-chloro-2,3-dihydropyridazine [4,5-b]quinoline-1,4-dione 5-oxide salt and 2-hydroxy-N,N,N-trimethyl -ethylammonium; N'-[2-chloro-5-(methylthio)phenyl]-N-methyl-N-[3-(methylthio)phenyl]-anthracene;N'-[2- Chloro-5-(methylthio)phenyl]-N-methyl-N-[3-[( R )-methylsulfinyl]phenyl]-indole; 6-chloro-2,3,4 ,9-tetrahydro-9-methyl-2,3-di-oxy-1H-indolo[1,2-b]pyrazine-9-acetic acid; 7-chlorosulfuric uric acid; (3 S , 4a R ,6 S ,8a R )-decahydro-6-(phosphomethyl)-3-isoquinolinecarboxylic acid; (-)-6,7-dichloro-1,4-dihydro-5-[3 -(methoxymethyl)-5-(3-pyridyl)-4-H-1,2,4-triazol-4-yl]-2,3-quinoxalinedione; 4,6- Dichloro-3-[(E)-(2-o-oxy-1-phenyl-3-pyrrolidinyl)methyl]-1H-indole-2-carboxylic acid; (2 R , 4 S )- Rel-5,7-dichloro-1,2,3,4-tetrahydro-4-[[(phenylamino)carbonyl]amino]-2-quinolinecarboxylic acid; (3 R , 4 S ) -rel-3,4-dihydro-3-[4-hydroxy-4-(phenylmethyl)-1-pyrrolidinyl]-2H-1-benzopipene-4,7-diol; -[(2,3-dihydro-1H-indol-2-yl)amino]-acetamide; 1,4-dihydro-6-methyl-5-[(methylamino)methyl] -7-nitro-2,3-quinoxalinedione; [2-(8,9-di- oxo-2,6-diazabicyclo[5.2.0]壬-1(7)- 2-yl) ethyl] - phosphonic acid; (2 R, 6 S) -1,2,3,4,5,6- hexahydro -3 - [(2S) -2- methoxypropyl] -6,11,11-trimethyl-2,6-methanol-3-phenylzaxin-9-ol; 2-hydroxy-5-[[(pentafluorophenyl)methyl]amino]-benzene Formic acid; 1-[2-(4-hydroxyphenoxy)ethyl]-4-[(4-methylphenyl)methyl]-4-piperidinol; 1-[4-(1H-imidazole- 4-yl)-3-butynyl]-4-(phenylmethyl)-piperidine; 2-methyl-6-(phenylethynyl)-pyridine; 3-(phosphomethyl)-L- Phenylalanine; or 3,6,7-tetrahydro-2,3-di-oxy-N-phenyl-1H,5H-pyrido[1,2,3-de]quinoxaline-5- Acetamide. The method of claim 18, wherein the method further comprises administering to the mammal a cholecystokinin B antagonist. The use of claim 18, wherein the use further comprises administering to the mammal a substance P antagonist. The use of claim 18, wherein the use further comprises administering to the mammal an anti-inflammatory compound. The method of claim 62, wherein the anti-inflammatory compound is: aspirin, celecoxih, cortisone, deracoxib, diflunisal, etoricoxib, fenoprofen, ibuprofen, ketoprofen, Naproxen, prednisolone, sulindac, tolmetin, piroxicam, Mefenamic acid, Meloxicam, phenylbutazone, Rofecoxib, suprofen, valdecoxib, 4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide, N-[2-(cyclohexyloxy)- 4-nitrophenyl]methanesulfonamide, 2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methylbutoxy)-5-[4-(methylsulfonate) Mercapto)phenyl]-3(2H)-tetrahydropyridazinone, or 2-(3,5-difluorophenyl)-3-[4-(methylsulfonyl)phenyl]-2- Cyclopenten-1-one. The use of claim 18, wherein the use further comprises administering to the mammal a DHP-sensitive L-type calcium channel antagonist, an omega-conotoxin-sensitive N-type calcium channel antagonist, or P/Q calcium channel antagonist. The use of claim 18, wherein the use further comprises administering to the mammal an adenosine kinase antagonist. The use of claim 18, wherein the use further comprises administering to the mammal an adenosine receptor A ₁ synergist, an adenosine receptor A _2a antagonist, or an adenosine receptor A ₃ Synergistic agent. The use of claim 18, wherein the use further comprises administering to the mammal an adenosine deaminase inhibitor. The use of claim 18, wherein the use further comprises administering to the mammal an adenosine nucleoside delivery inhibitor. The use of claim 18, wherein the use further comprises administering to the mammal a vanilloid VR1 receptor synergist. The use of claim 18, wherein the use further comprises administering a cannabinoid CB1/CB2 synergist to the mammal. The use of claim 18, wherein the use further comprises administering to the mammal an AMPA receptor antagonist. The use of claim 18, wherein the use further comprises administering to the mammal a kainate receptor antagonist. The use of claim 18, wherein the use further comprises administering a monosodium channel blocker to the mammal. The use of claim 18, wherein the use further comprises administering to the mammal a nicotinic acetylcholine receptor synergist. The use according to claim 18, wherein the application further comprises administering to the mammal a K _ATP potassium channel, a K _v1.4 potassium channel, a Ca ²⁺ -activated potassium channel, a SK potassium channel, and a BK. Potassium channel, IK potassium channel, or KCNQ2/3 potassium channel opener. The use according to claim 18, wherein the use further comprises administering to the mammal a muscarinic M3 antagonist, a muscarinic M1 synergist, or a muscarinic M2/M3 partial synergist/antagonism Agent. The use of claim 18, wherein the use further comprises administering an antioxidant to the mammal. The use of claim 18, wherein the use further comprises administering an antipsychotic to the mammal. The use according to claim 78, wherein the antipsychotic drugs are: promazine, chlorpromazine, chlorprothixene, thioridazine, acetophenazine, mesoridazine, droperidol, loxapine, molindone, Perphenazine, prochlorphenazine, thiothixene, trifluoperizine, fluphenazine, pimozide, flupenthixol, methotrimeprazine, pipotiazine, sertindole, clozapine, olanzapine, Risperidone, aripiprazole, quetiapine, haloperidol, ziprasidone, or iloperidone. The use of claim 18, wherein the use further comprises administering to the mammal a dopamine receptor anti-Parkinson's agent. The use of claim 80, wherein the anti-Parkinson's agent is levodopa or pramipexole. The use of claim 18, wherein the use further comprises administering to the mammal a fatty guanamine hydrolase (FAAH) inhibitor. The compound of claim 1 or 2, wherein R ¹ or R ⁶ is a randomly substituted C _1-6 alkyl group, including -NR ^G R ^H , wherein each R ^G and R ^{H are} each ( a) hydrogen, (b) optionally substituted C _1-6 alkyl, or (c) optionally substituted C _3-8 cycloalkyl. The compound of claim 83, wherein (b) the optionally substituted C _1-6 alkyl group is a hydroxyalkyl group or an unsubstituted C _1-6 alkyl group. a compound having the formula: Or a pharmaceutically acceptable salt. A pharmaceutical composition comprising a compound having the formula: Or a pharmaceutically acceptable salt, and a pharmaceutically acceptable excipient. The compound of claim 86, wherein the composition is formulated for topical administration. The use of claim 21, wherein the 5-HT _1D/1B synergist is a triptan.